Indazole compounds useful as protein kinase inhibitors

ABSTRACT

The present invention provides compounds of formula I: 
                         
or a pharmaceutically acceptable derivative thereof, wherein R 1 , R 2 , V 1 , V 2 , and V 3  are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of AKT, PKA, PDK1, p70S6K, or ROCK kinase, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions in the treatment of various disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 60/351,597 filed Jan. 25, 2002, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, the compounds are inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK kinases and are useful for treating diseases, such as cancer.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases.

Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.

Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. A challenge has been to find protein kinase inhibitors that act in a selective manner. Since there are numerable protein kinases that are involved in a variety of cellular responses, non-selective inhibitors may lead to unwanted side effects.

AKT (also known as PKB or Rac-PK beta), a serine/threonine protein kinase, has been shown to be overexpressed in several types of cancer and is a mediator of normal cell functions [(Khwaja, A., Nature, 401, pp. 33–34, 1999); (Yuan, Z. Q., et al., Oncogene, 19, pp. 2324–2330, 2000); (Namikawa, K., et al., J. Neurosci., 20, pp. 2875–2886, 2000)]. AKT comprises an N-terminal pleckstrin homology (PH) domain, a kinase domain and a C-terminal “tail” region. Three isoforms of human AKT kinase (AKT-1, -2 and -3) have been reported so far [(Cheng, J. Q., Proc. Natl. Acad. Sci. USA, 89, pp. 9267–9271, 1992); (Brodbeck, D. et al., J. Biol. Chem. 274, pp. 9133–9136, 1999)]. The PH domain binds 3-phosphoinositides, which are synthesized by phosphatidyl inositol 3-kinase (PI3K) upon stimulation by growth factors such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor (IGF-1) [(Kulik et al., Mol. Cell. Biol., 17, pp. 1595–1606, 1997); (Hemmings, B. A., Science, 275, pp. 628–630, 1997)]. Lipid binding to the PH domain promotes translocation of AKT to the plasma membrane and facilitates phosphorylation by another PH-domain-containing protein kinases, PDK1 at Thr308, Thr309, and Thr305 for the AKT isoforms 1, 2 and 3, respectively. A second, as of yet unknown, kinase is required for the phosphorylation of Ser473, Ser474 or Ser472 in the C-terminal tails of AKT-1, -2 and -3 respectively, in order to yield a fully activated AKT enzyme.

Once localized to the membrane, AKT mediates several functions within the cell including the metabolic effects of insulin (Calera, M. R. et al., J. Biol. Chem., 273, pp. 7201–7204, 1998), induction of differentiation and/or proliferation, protein synthesisans stress responses (Alessi, D. R. et al., Curr. Opin. Genet. Dev., 8, pp. 55–62, 1998).

Manifestations of altered AKT regulation appear in both injury and disease, the most important role being in cancer. The first account of AKT was in association with human ovarian carcinomas where expression of AKT was found to be amplified in 15% of cases (Cheng, J. Q. et al., Prod. Natl. Acad. Sci. U.S.A., 89, pp. 9267–9271, 1992). It has also been found to be overexpressed in 12% of pancreatic cancers (Cheng, J. Q. et al., Proc. Natl. Acad. Sci. U.S.A., 93, pp. 3636–3641, 1996). It was demonstrated that AKT-2 was over-expressed in 12% of ovarian carcinomas and that amplification of AKT was especially frequent in 50% of undifferentiated tumours, suggesting that AKT may also be associated with tumour aggressiveness (Bellacosa, et al., Int. J. Cancer, 64, pp. 280–285, 1995).

PKA (also known as cAMP-dependent protein kinase) has been shown to regulate many vital functions including energy metabolism, gene transcription, proliferation, differentiation, reproductive function, secretion, neuronal activity, memory, contractility and motility (Beebe, S. J., Semin. Cancer Biol., 5, pp. 285–294, 1994). PKA is a tetrameric holoenzyme, which contains two catalytic subunits bound to a homo-dimeric regulatory subunit (which acts to inhibit the catalytic sub-units). On binding of cAMP (enzyme activation), the catalytic subunits dissociate from the regulatory subunits to yield the active serine/threonine kinase (McKnight, G. S. et al., Recent Prog. Horm. Res., 44, pp. 307, 1988). Three isoforms of the catalytic subunit (C-α, C-β and C-γ have been reported to date (Beebe, S. J. et al., J. Biol. Chem., 267, pp. 25505–25512, 1992) with the C-α subunit being the most extensively studied, primarily because of its elevated expression in primary and metastatic melanomas (Becker, D. et al., Oncogene, 5, pp. 1133, 1990). To date, strategies to modulate the activity of the C-α subunit involve the use of antibodies, molecules that block PKA activity by targeting regulatory dimers and antisense oligonucleotides expression.

Rho-associated coiled-coil forming kinase (ROCK) (Ishizaki, T. et al., EMBO J., 15, pp. 1885–1893, 1996) is a 160 kDa serine/threonine kinase that activates the small G-protein RhoA. ROCK has been implicated in numerous diseases including hypertension [(Chitaley, et al., Curr. Hypertens. Rep. 2001 Apr., 3(2), pp.139–144); (Uehata, M. et al., Nature, 389, pp. 990–994, 1997)], erectile dysfunction (Chitaley, K. et al., Nature Medicine, 7, pp. 119–122, 2001), angiogenesis (Uchida, S. et al., Biochem. Biophys. Res. Commun., 269 (2), pp. 633–40, 2000), neuroregeneration (Bito, H. et al., Neuron, 26, pp. 431–441, 2000), metastasis [(Takamura, M. et al., Hepatology, 33, pp. 577–581, 2001); (Genda, T. et al., Hepatology, 30, pp. 1027–1036, 1999)], glaucoma (Rao, et al., Invest. Ophthalmol. Vis. Sci., 42, pp. 1029–37, 2001), inflammation (Ishizuka, T. et al., J. Immunol., 167, pp. 2298–2304, 2001), arteriosclerosis (Smimokawa, et al., Arterioscler. Thromb. Vasc. Biol., 11, pp. 2351–2358, 2000), immunosuppresion (Lou, Z. et al., J. Immunol., 167, pp. 5749–5757, 2001), restenosis (Seaholtz, et al., Circ. Res., 84, pp. 1186–1193, 1999), asthma (Yoshii, et al., Am. J. Respir. Cell Mol. Biol., 20, pp. 1190–1200, 1999), cardiac hypertrophy (Kuwahara, K. et al., FEBS Lett., 452, pp. 314–318, 1999).

The ribosomal protein kinases p70S6K-1 and -2 are members of the AGC sub-family of protein kinases that consists of, amongst others, PKB and MSK. The p70S6 kinases catalyze the phosphorylation and subsequent activation of the ribosomal protein S6, which has been implicated in the translational up-regulation of mRNAs coding for the components of protein synthetic apparatus.

These mRNAs contain an oligopyrimidine tract at their 5′ transcriptional start site, termed a 5TOP, which has been shown to be essential for their regulation at the translational level (Volarevic, S. et al., Prog. Nucleic Acid Res. Mol. Biol. 65, pp 101–186, 2001). p70 S6K dependent S6 phosphorylation is stimulated in response to a variety of hormones and growth factors primarily via the P13K pathway (Coffer, P. J. et al., Biochem. Biophys. Res. Commun, 198, 7 pp 780–786, 1994), which maybe under the regulation of mTOR, since rapamycin acts to inhibit p70S6K activity and blocks protein synthesis, specifically as a result of a down-regulation of translation of these mRNA's encoding ribosomal proteins (Kuo, C. J. et al., Nature, 358, pp 70–73, 1992).

In vitro PDK1 catalyses the phosphorylation of Thr252 in the activation loop of the p70 catalytic domain, which is indispensable for p70 activity (Alessi, D. R., Curr. Biol., 8, pp 69–81, 1998). The use of rapamycin and gene deletion studies of dp70S6K from Drosophila and p70S6K1 from mouse have established the central role p70 plays in both cell growth and proliferation signaling.

The 3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a key role in regulating the activity of a number of kinases belonging to the AGC subfamily of protein kinases (Alessi, D. et al., Biochem. Soc. Trans, 29, pp. 1, 2001). These include isoforms of protein kinase B (PKB, also known as AKT), p70 ribosomal S6 kinase (S6K) (Avruch, J. et al., prog. Mol. Subcell. Biol., 2001, 26, pp. 115, 2001), and p90 ribosomal S6 kinase (Frödin, M. et al., EMBO J., 19, pp. 2924–2934, 2000). PDK1 mediated signaling is activated in response to insulin and growth factors and as a consequence of attachment of the cell to the extracellular matrix (integrin signaling). Once activated these enzymes mediate many diverse cellular events by phosphorylating key regulatory proteins that play important roles controlling processes such as cell survival, growth, proliferation and glucose regulation [(Lawlor, M. A. et al., J. Cell Sci., 114, pp. 2903–2910, 2001), (Lawlor, M. A. et al., EMBO J., 21, pp. 3728–3738, 2002)]. PDK1 is a 556 amino acid protein, with an N-terminal catalytic domain and a C-terminal pleckstrin homology (PH) domain, which activates its substrates by phosphorylating these kinases at their activation loop (Belham, C. et al., Curr. Biol., 9, pp. R93–R96, 1999). Many human cancers including prostate and NSCL have elevated PDK1 signaling pathway function resulting from a number of distinct genetic events such as PTEN mutations or over-expression of certain key regulatory proteins [(Graff, J. R., Expert Opin. Ther. Targets, 6, pp. 103–113, 2002), (Brognard, J., et al., Cancer Res., 61, pp. 3986–3997, 2001)]. Inhibition of PDK1 as a potential mechanism to treat cancer was demonstrated by transfection of a PTEN negative human cancer cell line (U87MG) with antisense oligonucleotides directed against PDK1. The resulting decrease in PDK1 protein levels led to a reduction in cellular proliferation and survival (Flynn, P., et al., Curr. Biol., 10, pp. 1439–1442, 2000). Consequently the design of ATP binding site inhibitors of PDK1 offers, amongst other treatments, an attractive target for cancer chemotherapy.

The diverse range of cancer cell genotypes has been attributed to the manifestation of the following six essential alterations in cell physiology: self-sufficiency in growth signaling, evasion of apoptosis, insensitivity to growth-inhibitory signaling, limitless replicative potential, sustained angiogenesis, and tissue invasion leading to metastasis (Hanahan, D. et al., Cell, 100, pp. 57–70, 2000). PDK1 is a critical mediator of the P13K signalling pathway, which regulates a multitude of cellular function including growth, proliferation and survival. Consequently inhibition of this pathway could affect four or more of the six defining requirements for cancer progression, as such it is anticipated that a PDK1 inhibitor will have an effect on the growth of a very wide range of human cancers.

Specifically, increased levels of PI3K pathway activity has been directly associated with the development of a number of human caners, progression to an aggressive refractory state (acquired resistance to chemotherapies) and poor prognosis. This increased activity has been attributed to a series of key events including decreased activity of negative pathway regulators such as the phosphatase PTEN, activating mutations of positive pathway regulators such as Ras, and overexpression of components of the pathway itself such as PKB, examples include: brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, thyroid [(Teng, D. H. et al., Cancer Res., 57, pp. 5221–5225, 1997), (Brognard, J. et al., Cancer Res., 61, pp. 3986–3997, 2001), (Cheng, J. Q. et al., Proc. Natl. Acad. Sci., 93, pp. 3636–3641, 1996), Int. J. Cancer, 64, pp. 280, 1995), (Graff, J. R., Expert Opin. Ther. Targets, 6, pp. 103–113, 2002), Am. J. Pathol., 159, pp. 431, 2001)].

Additionally, decreased pathway function through gene knockout, gene knockdown, dominant negative studies and small molecule inhibitors of the pathway have been demonstrated to reverse many of the cancer phenotypes in vitro (some studies have also demonstrated a similar effect in vivo) such as block proliferation, reduce viability and sensitize cancer cells to known chemotherapies in a series of cell lines, representing the following cancers: pancreatic [(Cheng, J. Q. et al., Proc. Natl. Acad. Sci., 93, pp. 3636–3641, 1996), Neoplasia, 3, pp. 278, 2001)], lung [(Brognard, J. et al., Cancer Res., 61, pp. 3986–3997, 2001), Neoplasia, 3, pp. 278, 2001)], ovarian [(Hayakawa, J. et al., Cancer Res., 60, pp. 5988–5994, 2000), Neoplasia, 3, pp. 278, 2001)], breast (Mol. Cancer Ther., 1, pp. 707, 2002), colon [(Neoplasia, 3, pp. 278, 2001), (Arico, S. et al., J. Biol. Chem., 277, pp. 27613–27621, 2002)], cervical (Neoplasia, 3, pp. 278, 2001), prostate [(Endocrinology, 142, pp. 4795, 2001), (Thakkar, H. et al. J. Biol. Chem., 276, pp. 38361–38369, 2001), (Chen, X. et al., Oncogene, 20, pp. 6073–6083, 2001)] and brain (glioblastomas) [(Flynn, P. et al., Curr. Biol., 10, pp. 1439–1442, 2000)].

Accordingly, there is a great need to develop inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK protein kinases that are useful in treating various diseases or conditions associated with AKT, PKA, PDK1, p70S6K, and ROCK activation, particularly given the inadequate treatments currently available for the majority of these disorders.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK protein kinases. These compounds have the formula I:

or a pharmaceutically acceptable salt thereof, wherein V¹, V², V³, R¹, and R² are as defined below.

These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders, including allergic disorders such as asthma, inflammatory disease, proliferative disorders, and neurological disorders.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from halogen, CN, N(R⁴)₂, T-R, or T-Ar; -   each T is independently selected from a valence bond or a C₁₋₆     alkylidene chain, wherein up to two methylene units of T are     optionally, and independently, replaced by —O—, —N(R)—, —S—,     —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO₂—; -   each R is independently selected from hydrogen or an optionally     substituted C₁₋₆ aliphatic group, or:     -   two R groups on the same nitrogen, taken together with the         nitrogen atom attached thereto, form a 5–7 membered saturated,         partially unsaturated, or aromatic ring having 1–3 heteroatoms         independently selected from nitrogen, oxygen, or sulfur; -   R² is selected from Q-Ar, Q-N(R⁵)₂, or Q-C(R)(Q-Ar)R³, wherein:     -   R and R³ optionally form a 5–7 membered saturated or partially         unsaturated ring having 0–4 heteroatoms independently selected         from nitrogen, oxygen, or sulfur; -   each Q is independently selected from a valence bond or a C₁₋₄     alkylidene chain; -   each Ar is independently an optionally substituted ring selected     from a 5–7 membered saturated, partially unsaturated, or fully     unsaturated monocyclic ring having 0–4 heteroatoms independently     selected from nitrogen, oxygen, or sulfur, or an 8–10 membered     saturated, partially unsaturated, or fully unsaturated bicyclic ring     having 0–4 heteroatoms independently selected from nitrogen, oxygen,     or sulfur; -   R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵,     Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or     N(R)Q-N(R⁴)₂; -   R′ is an optionally substituted C₁₋₆ aliphatic group; -   each R⁴ is independently selected from R, COR⁵, CO₂R⁵, CON(R⁵)₂,     SO₂R⁵, SO₂N(R⁵)₂, or Ar¹; -   each R⁵ is independently selected from R or Ar; -   V¹, V² and V³ are each independently selected from nitrogen or     C(R⁶); -   each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR,     SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂,     OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or     SO₂N(R⁴)₂; and -   each Ar¹ is independently selected from an optionally substituted     5–7 membered saturated, partially unsaturated, or fully unsaturated     monocyclic ring having 0–4 heteroatoms independently selected from     nitrogen, oxygen, or sulfur; -   provided that: -   when V¹, V², and V³ are each CH, T is a valence bond, and R² is     Q-C(R)(Q-Ar)R³, wherein Ar is an optionally substituted phenyl ring,     then R³ is other than Q-OR⁵ or C(O)NH₂; and -   when V¹, V², and V³ are each CH and R¹ is hydrogen then R² is     Q-C(R)(Q-Ar)R³, wherein R³ is other than R′, Q-OC(O)R⁵, or     OCH₂phenyl.

As used herein, the following definitions shall apply unless otherwise indicated. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

The term “aliphatic” or “aliphatic group” as used herein means a straight-chain or branched C₁–C₁₂ hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C₃–C₈ hydrocarbon or bicyclic C₈–C₁₂ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, hut which is not aromatic (also referred to herein as “carbocycle” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3–7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term “nitrogen” includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0–4 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, oxo, N₃, —R°, —OR°, —SR°, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), Ph substituted with R°, —O(Ph), O—(Ph) substituted with R°, —CH₂(Ph), —CH₂(Ph) substituted with R°, —CH₂CH₂(Ph), —CH₂CH₂(Ph) substituted with R°, —NO₂, —CN, —N(R°)₂, —NR°C(O)R°, —NR°C(O)N(R°)₂, —NR°CO₂R°, —NR°NR°C(O)R°, —NR°NR°C(O)N(R°)₂, —NR°NR°CO₂R°, —C(O)C(O)R°, —C(O)CH₂C(O)R°, —CO₂R°, —C(O)R°, —C(O)N(R°)₂, —OC(O)N(R°)₂, —S(O)₂R°, —SO₂N(R°)₂, —S(O)R°, —NR°SO₂N(R°)₂, —NR°SO₂R°, —C(═S)N(R°)₂, —C(═NH)—N(R°)₂, or —(CH₂)_(y)NHC(O)R°, wherein y is 0–4, each R° is independently selected from hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5–6 membered heteroaryl or heterocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl (Ph), —O(Ph), or —CH₂(Ph)—CH₂(Ph). Substituents on the aliphatic group of R° are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═N—, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic. Substituents on the aliphatic group of R* are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

Substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl (Ph), optionally substituted —O(Ph), optionally substituted —CH₂(Ph), optionally substituted —CH₂CH₂(Ph), or an unsubstituted 5–6 membered heteroaryl or heterocyclic ring. Substituents on the aliphatic group or the phenyl ring of R⁺ are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

The term “alkylidene chain” refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of connection to the rest of the molecule.

The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

Compounds of this invention may exist in alternative tautomeric forms. Unless otherwise indicated, the representation of either tautomer is meant to include the other.

One embodiment of the present invention relates to a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are as defined above for compounds of formula I.

According to one preferred embodiment, the present invention relates to a compound of formula I wherein V¹ is N, V² is CH, and V³ is CH.

Preferred compounds of formula I include those wherein V¹ is C—R⁶, V² is CH, and V³ is CH or N.

Another preferred embodiment of the present invention relates to a compound of formula I wherein V¹ is C—R⁶, V² is CH, and V³ is N.

Another preferred embodiment of the present invention relates to a compound of formula I wherein V¹ is C—R⁶, V² is CH, and V³ is CH.

According to another preferred embodiment, the present invention relates to a compound of formula Ia wherein V² is CH and V³ is N.

According to another preferred embodiment, the present invention relates to a compound of formula Ia wherein V² and V³ are each N.

Preferred R¹ groups of formula I or Ia include hydrogen, halogen, CN, N(R⁴)₂, and optionally substituted C₁₋₆ aliphatic. Examples of such R¹ groups include chloro, bromo, fluoro, NH₂, NHME, NHEt, NH—(optionally substituted phenyl), NH-cyclohexyl, NHCH₂(optionally substituted phenyl), NHC(O)(optionally substituted phenyl), NHC(O)NH(optionally substituted phenyl), NHC(O)CH₂(optionally substituted phenyl), NHC(O)CH₂CH₂(optionally substituted phenyl), N(R)C(O)(optionally substituted phenyl), NHC(O)naphthyl, NHC(O)thienyl, NRC(O)thienyl, SC(O)thienyl, CH₂C(O)thienyl, NHC(O)pyridyl, NHC(O)furanyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, and t-butyl.

The optional substituents of the phenyl rings of R¹ of formula I or Ia, when present, are optionally substituted R°, halogen, nitro, CN, OR°, SR°, N(R°)₂, SO₂R°, C(O)R°, C(O)OR, and C(O)N(R°)₂, wherein each R° is as defined supra. Examples of such groups include chloro, bromo, fluoro, CN, nitro, OMe, OPh, OCF₃, OCH₂Ph, OEt, SCHF₂, methyl, ethyl, isopropyl, propyl, vinyl, CF₃, acetylenyl, CH₂Ph, CH₂NH₂, CH₂N(Et)₂, CH₂morpholin-4-yl, CH₂piperidin-1-yl, CH₂imidazol-1-yl, CH₂piperazin-1-yl, C(O)NH₂, C(O)Me, SO₂Me, NHEt, and NHMe.

When R¹ of formula I or Ia is T-Ar, preferred Ar groups are selected from an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such Ar rings include optionally substituted phenyl, thienyl, furan, and pyridyl rings. Preferred T moieties of the T-Ar group of R¹ are selected from a valence bond, —N(R)C(O)—, —NH—, —NHCH₂—, —NHSO₂—, —CH₂NH—, —SC(O)—, —CH₂C(O)—, —C≡C—, —CH₂— or —CH₂CH₂—. More preferred T moieties of the T-Ar group of R¹ are selected from —NHC(O)—, —NH—, —NHCH₂—, —CH₂—, —C≡C—, or —CH₂CH₂—. Most preferred T moieties of the T-Ar group of R¹ are selected from —N(R)C(O)—, —NH—, or —NHCH₂—. Preferred substituents on the Ar group, when present, include fluoro and CF₃, Me, Et, iPr, vinyl, acetylene, Ar, Cl, CF₃, nitro, CN, OMe, OPh, OCF₃, SO₂NH2, C(O)OEt, C(O)OH, CH₂CO₂H, CH₂CH₂CO₂H, CH₂NH₂ and C(O)NH₂, thienyl, oxazolyl, isoxazolyl, and tetrazolyl.

Preferred Q groups of formula I or Ia are selected from a valence bond, —CH₂—, or —CH₂CH₂—.

When R² of formula I or Ia is Q-Ar, preferred Ar groups are an optionally substituted ring selected from a 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, pyrimidinyl, pyridonyl, furanyl, tetrazolyl, thienyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, indan-1-onyl, naphthyl, benzothiophenyl, 2,3-dihydro-1H-isoindolyl, indanyl, benzofuranyl, and indolyl.

When present, preferred substituents on the Ar ring of R² include R°, halogen, oxo, OR°, phenyl, optionally substituted dialkylamino, haloalkyl, C(O)R°, NHC(O)R, or SR°. Examples of such preferred substituents include chloro, bromo, fluoro, OH, OMe, NHC(O)CH₃, OEt, C(O)phenyl, Ophenyl, N(CH₂CH₂Cl)₂, N(Me)₂, CF₃, and SCF₃. Other examples of preferred Ar groups of formula I or Ia also include those shown in Table 1 below.

When the R² group of formula I or Ia is Q-C(R)(Q-Ar)R³, preferred R³ groups include R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, and N(R)Q-N(R⁴)₂. Examples of such R³ groups include CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

More preferably, the R³ group of formula I or Ia is selected from OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

Most preferably, the R³ group of formula I or Ia is selected from CH₂CH₂NH₂.

Preferred rings formed by the R and R³ moieties of the Q-C(R)(Q-Ar)R³ group of R² are selected from a 5–6 membered saturated ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R³ include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

When the R² group of formula I or Ia is Q-C(R)(Q-Ar)R³, preferred Ar groups of the Q-C(R)(Q-Ar)R³ moiety are selected from an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, furanyl, pyridone, and thienyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, naphthyl, indanyl, and indolyl. When present, preferred substituents on the Ar ring of the Q-C(R)(Q-Ar)R³ group of R² include R°, halogen, OR°, phenyl, N(R°)₂, NHC(O)R°, or SR°. Examples of such groups include fluoro, chloro, bromo, CF₃, OH, OMe, OPh, OCH₂Ph, SMe, NH₂, NHC(O)Me, methyl, ethyl, isopropyl, isobutyl, and cyclopropyl.

Preferred R⁶ groups of formula I or Ia, when present, are selected from halogen, R, and Ar¹. More preferred R⁶ groups of formula I or Ia, when present, are selected from halogen, optionally substituted C₁₋₄ aliphatic, or an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such groups include chloro, bromo, methyl, ethyl, t-butyl, cyclopropyl, isopropyl, phenyl, and pyridyl.

According to another embodiment, the present invention relates to a compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from halogen, CN, N(R⁴)₂, T-R, or T′-Ar; -   T is selected from a valence bond or a C₁₋₆ alkylidene chain,     wherein up to two methylene units of T are optionally, and     independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—,     —C(O)—, or —SO₂—; -   T′ is a C₁₋₆ alkylidene chain, wherein up to two methylene units of     T′ are optionally, and independently, replaced by —O—, —N(R)—, —S—,     —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO₂—; -   each R is independently selected from hydrogen or an optionally     substituted C₁₋₆ aliphatic group, or:     -   two R groups on the same nitrogen, taken together with the         nitrogen atom attached thereto, form a 5–7 membered saturated,         partially unsaturated, or aromatic ring having 1–3 heteroatoms         independently selected from nitrogen, oxygen, or sulfur; -   R² is selected from Q-Ar, Q-N(R⁵)₂, or Q-C(R)(Q-Ar)R³, wherein:     -   R and R³ optionally form a 5–7 membered saturated or partially         unsaturated ring having 0–4 heteroatoms independently selected         from nitrogen, oxygen, or sulfur; -   each Q is independently selected from a valence bond or a C₁₋₄     alkylidene chain; -   each Ar is independently an optionally substituted ring selected     from a 5–7 membered saturated, partially unsaturated, or fully     unsaturated monocyclic ring having 0–4 heteroatoms independently     selected from nitrogen, oxygen, or sulfur, or an 8–10 membered     saturated, partially unsaturated, or fully unsaturated bicyclic ring     having 0–4 heteroatoms independently selected from nitrogen, oxygen,     or sulfur; -   R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵,     Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or     N(R)Q-N(R⁴)₂; -   R′ is an optionally substituted C₁₋₆ aliphatic group; -   each R⁴ is independently selected from R, COR⁵ CO₂R⁵ CON(R⁵)₂,     SO₂R⁵, SO₂N(R⁵)₂, or Ar¹; -   each R⁵ is independently selected from R or Ar; -   V¹, V² and V³ are each independently selected from nitrogen or     C(R⁶); -   each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR,     SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂,     OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or     SO₂N(R⁴)₂; and -   each Ar¹ is independently selected from an optionally substituted     5–7 membered saturated, partially unsaturated, or fully unsaturated     monocyclic ring having 0–4 heteroatoms independently selected from     nitrogen, oxygen, or sulfur; -   provided that:     -   when V¹, V², and V³ are each CH and R¹ is hydrogen, then R² is         Q-C(R)(Q-Ar)R³, wherein R³ is other than R′, Q-OC(O)R⁵, or         OCH₂phenyl.

Preferred R¹ and R² groups of formula I′ are those described above for compounds of formulae I and Ia. When R¹ is T′-Ar, preferred T′ groups of formula I′ are selected from —NHC(O)—, —NH—, —NHCH₂—, —NHSO₂—, —CH₂NH—, —CH₂—, —C≡C—, or —CH₂CH₂—. More preferred T′ groups of formula I′ are selected from —NHC(O)—, —NH—, —NHCH₂—, —NHSO₂—, or —CH₂NH—.

According to another embodiment, the present invention relates to a compound of formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R¹, R³, Q, and Ar are as defined above for compounds of formula I.

Preferred R¹ groups of formula Ib include those described above for compounds of formula I and Ia.

Preferred V¹, V², and V³ groups of formula Ib are the preferred V¹, V², and V³ groups set forth for compounds of formula I, supra.

Preferred Q groups of formula Ib include those described above for compounds of formula I and Ia.

Preferred Ar groups of formula Ib include an optionally substituted ring selected from a 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, thienyl, furanyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, indan-1-onyl, naphthyl, benzothiophenyl, 2,3-dihydro-1H-isoindolyl, indanyl, benzofuranyl, and indolyl. When present, preferred substituents on the Ar group of formula Ib include R°, halogen, OR°, phenyl, optionally substituted dialkylamino, haloalkyl, C(O)R°, or SR°. Examples of such preferred substituents include tetrazolyl, oxazolyl, isoxazolyl, chloro, bromo, fluoro, OH, OMe, OEt, C(O)phenyl, Ophenyl, N(CH₂CH₂Cl)₂, N(Me)₂, CF₃, and SCF₃.

Preferred R³ groups of formula Ib include R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, and N(R)Q-N(R⁴)₂. Examples of such R³ groups include CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

More preferably, the R³ group of formula Ib is selected from OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

Most preferably, the R³ group of formula Ib is selected from CH₂CH₂NH₂.

Preferred rings formed by the R and R³ moieties of the Q-C(R)(Q-Ar)R³ group of formula Ib are selected from a 5–6 membered saturated ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R³ include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

Another embodiment of the present invention relates to a compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from halogen, CN, N(R⁴)₂, or T-R; -   T is selected from a valence bond or a C₁₋₆ alkylidene chain,     wherein up to two methylene units of T are optionally, and     independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—,     —C(O)—, or —SO₂—; -   each R is independently selected from hydrogen or an optionally     substituted C₁₋₆ aliphatic group, or:     -   two R groups on the same nitrogen, taken together with the         nitrogen atom attached thereto, form a 5–7 membered saturated,         partially unsaturated, or aromatic ring having 1–3 heteroatoms         independently selected from nitrogen, oxygen, or sulfur; -   R² is Q-C(R)(Q-Ar)R³, wherein:     -   R and R³ optionally form a 5–7 membered saturated or partially         unsaturated ring having 0–4 heteroatoms independently selected         from nitrogen, oxygen, or sulfur; -   each Q is independently selected from a valence bond or a C₁₋₄     alkylidene chain; -   each Ar is independently an optionally substituted ring selected     from a 5–7 membered saturated, partially unsaturated, or fully     unsaturated monocyclic ring having 0–4 heteroatoms independently     selected from nitrogen, oxygen, or sulfur, or an 8–10 membered     saturated, partially unsaturated, or fully unsaturated bicyclic ring     having 0–4 heteroatoms independently selected from nitrogen, oxygen,     or sulfur; -   R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵,     Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or     N(R)Q-N(R⁴)₂; -   R′ is an optionally substituted C₁₋₆ aliphatic group; -   each R⁴ is independently selected from R, COR, CO₂R, CON(R)₂, SO₂R,     SO₂N(R)₂, or Ar¹; -   each R⁵ is independently selected from R or Ar; -   V¹, V² and V² are each independently selected from nitrogen or     C(R⁶); -   each R⁶ is independently selected from R, Ar¹, halogen CN, NO₂, OR,     SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂,     OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or     SO₂N(R⁴)₂; and -   each Ar¹ is independently selected from an optionally substituted     5–7 membered saturated, partially unsaturated, or fully unsaturated     monocyclic ring having 0–4 heteroatoms independently selected from     nitrogen, oxygen, or sulfur; -   provided that when R¹ is hydrogen then R³ is other than R′,     Q-OC(O)R⁵, or OCH₂phenyl.

Preferred R¹ groups of formula IIa include halogen, N(R⁴)₂, and optionally substituted C₁₋₆ aliphatic. Examples of such groups include chloro, bromo, fluoro, NH₂, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, and t-butyl.

Preferred V¹, V², and V³ groups of formula IIa are the preferred V¹, V², and V³ groups set forth for compounds of formula I, supra.

Preferred Q groups of formula IIa are selected from a valence bond, —CH₂—, or —CH₂CH₂—.

Preferred R³ groups of formula IIa include R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, and N(R)Q-N(R⁴)₂. Examples of such R³ groups include CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

More preferably, the R³ group of formula IIa is selected from OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

Most preferably, the R³ group of formula IIa is selected from CH₂CH₂NH₂.

Preferred rings formed by the R and R³ moieties of R² of formula IIa are selected from a 5–6 membered saturated ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R³ include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

Preferred Ar groups of R² of formula IIa are selected from an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, furanyl, and thienyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, naphthyl, indanyl, and indolyl. When present, preferred substituents on the Ar ring of the Q-C(R)(Q-Ar)R³ group of R² of formula IIa include R°, halogen, OR°, phenyl, N(R°)₂, NHC(O)R°, or SR°. Examples of such groups include fluoro, chloro, bromo, CF₃, OH, OMe, OPh, OCH₂PH, SMe, NH₂, NHC(O)Me, methyl, ethyl, isopropyl, isobutyl, and cyclopropyl.

Another embodiment relates to a compound of formula IIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is T-Ar; -   each T is independently selected from a valence bond or a C₁₋₆     alkylidene chain, wherein up to two methylene units of T are     optionally, and independently, replaced by —O—, —N(R)—, —S—,     —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO₂—; -   each R is independently selected from hydrogen or an optionally     substituted C₁₋₆ aliphatic group, or:     -   two R groups on the same nitrogen, taken together with the         nitrogen atom attached thereto, form a 5–7 membered saturated,         partially unsaturated, or aromatic ring having 1–3 heteroatoms         independently selected from nitrogen, oxygen, or sulfur; -   R² is Q-C(R)(Q-Ar)R³, wherein:     -   R and R³ optionally form a 5–7 membered saturated or partially         unsaturated ring having 0–4 heteroatoms independently selected         from nitrogen, oxygen, or sulfur; -   each Q is independently selected from a valence bond or a C₁₋₄     alkylidene chain; -   each Ar is independently an optionally substituted ring selected     front a 5–7 membered saturated, partially unsaturated, or fully     unsaturated monocyclic ring having 0–4 heteroatoms independently     selected from nitrogen, oxygen, or sulfur, or an 8–10 membered     saturated, partially unsaturated, or fully unsaturated bicyclic ring     having 0–4 heteroatoms independently selected from nitrogen, oxygen,     or sulfur; -   R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵,     Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or     N(R)Q-N(R⁴)₂; -   R′ is an optionally substituted C₁₋₆ aliphatic group; -   each R⁴ is independently selected from R, COR⁵, CO₂R⁵, CON(R⁵)₂,     SO₂R⁵, SO₂N(R⁵)₂, or Ar¹; -   each R⁵ is independently selected from R or Ar; -   V¹, V² and V³ are each independently selected from nitrogen or     C(R⁶); -   each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR,     SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂,     OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or     SO₂N(R⁴)₂; and -   each Ar¹ is independently selected from an optionally substituted     5–7 membered saturated, partially unsaturated, or fully unsaturated     monocyclic ring having 0–4 heteroatoms independently selected from     nitrogen, oxygen, or sulfur; -   provided that when V¹, V², and V³ are each CH, T is a valence bond,     and R² is Q-C(R)(Q-Ar)R³, wherein Ar is an optionally substituted     phenyl ring, then R³ is other than Q-OR⁵ or C(O)NH₂.

Preferred V¹, V², and V³ groups of formula IIb are those set forth for compounds of formula I, supra.

Preferred Ar groups of R¹ of formula IIb are selected from an optionally substituted 5–6 membered aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred T moieties of the T-Ar group of R¹ of formula IIb are selected from a valence bond, —NHC(O)—, —NH—, —NHCH₂—, —NHSO₂—, —CH₂NH—, —C≡C—, —CH₂— or —CH₂CH₂—. Most preferred T moieties of the T-Ar group of R¹ are selected from —NHC(O)—, —NH—, —NHCH₂—, —CH₂— or —CH₂CH₂—. Examples of R¹ groups of formula IIb include NHCH₂(optionally substituted phenyl), NHC(O)(optionally substituted phenyl), NHC(O)NH(optionally substituted phenyl), NHC(O)CH₂(optionally substituted phenyl), NHC(O)CH₂CH₂(optionally substituted phenyl), NHC(O)(optionally substituted phenyl), NHC(O)naphthyl, NHC(O)thienyl, NHC(O)pyridyl, NHC(O)furanyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, and t-butyl.

Preferred substituents on the Ar group of R¹ of formula IIb, when present, include R°, halogen, nitro, CN, OR°, SR°, N(R°)₂, SO₂R°, C(O)R°, C(O)OR, and C(O)N(R°)₂, wherein each R° is as defined supra. Examples of such groups include chloro, bromo, fluoro, CN, nitro, OMe, OPh, OCF₃, OCH₂Ph, OEt, SCHF₂, methyl, ethyl, isopropyl, propyl, vinyl, CF₃, acetylenyl, CH₂Ph, CH₂NH₂, CH₂N(Et)₂, CH₂morpholin-4-yl, CH₂piperdin-1-yl, CH₂imidazol-1-yl, CH₂piperazin-1-yl, C(O)NH₂, C(O)Me, SO₂Me, NHEt, and NHMe.

Preferred Q groups of formula IIb are those set forth above for compounds of formula I and Ib.

Preferred R³ groups of formula IIb include R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, and N(R)Q-N(R⁴)₂. Examples of such R³groups include CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

More preferably, the R³ group of formula IIb is selected from CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

Most preferably, the R³ group of formula IIb is selected from CH₂CH₂NH₂.

Preferred rings formed by the R and R³ moieties of R² of formula IIb are selected from a 5–6 membered saturated ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R³ include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

Preferred Ar groups of R² of formula IIb are selected from an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, pyrimidinyl, pyridonyl, furanyl, tetrazolyl, thienyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, indan-1-onyl, naphthyl, benzothiophenyl, 2,3-dihydro-1H-isoindolyl, indanyl, benzofuranyl, and indolyl. When present, preferred substituents on the Ar ring of the Q-C(R)(Q-Ar)R³ group of R² of formula IIb include R°, halogen, OR°, phenyl, N(R°)₂, NHC(O)R°, or SR°. Examples of such groups include fluoro, chloro, bromo, CF₃, OH, OMe, OPh, OCH₂PH, SMe, NH₂, NHC(O)Me, methyl, ethyl, isopropyl, isobutyl, and cyclopropyl.

According to another embodiment, the present invention relates to a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein R¹, R³, Q, and Ar are as defined above for compounds of formula I. Preferred V¹, V², V³, R¹, R³, Q, and Ar groups of formula III are those set forth above for compounds of formula I or Ib.

According to another embodiment, the present invention relates to a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein R¹, R³, Q, and Ar are as defined above for compounds of formula I. Preferred V¹, V², V³, R¹, R³, Q, and Ar groups of formula IV are those set forth above for compounds of formula I or Ib.

According to another embodiment, the present invention relates to a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R is independently selected from hydrogen or an optionally     substituted C₁₋₆ aliphatic group, or:     -   two R groups on the same nitrogen, taken together with the         nitrogen atom attached thereto, form a 5–7 membered saturated,         partially unsaturated, or aromatic ring having 1–3 heteroatoms         independently selected from nitrogen, oxygen, or sulfur; -   R² is Q-C(R)(Q-Ar)R³, wherein:     -   R and R³ optionally form a 5–7 membered saturated or partially         unsaturated ring having 0–4 heteroatoms independently selected         from nitrogen, oxygen, or sulfur; -   each Q is independently selected from a valence bond or a C₁₋₄     alkylidene chain; -   each Ar is independently an optionally substituted ring selected     from a 5–7 membered saturated, partially unsaturated, or fully     unsaturated monocyclic ring having 0–4 heteroatoms independently     selected from nitrogen, oxygen, or sulfur, or an 8–10 membered     saturated, partially unsaturated, or fully unsaturated bicyclic ring     having 0–4 heteroatoms independently selected from nitrogen, oxygen,     or sulfur; -   R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵,     Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or     N(R)Q-N(R⁴)₂; -   R′ is an optionally substituted C₁₋₆ aliphatic group; -   each R⁴ is independently selected from R, COR⁵, CO₂R⁵, CON(R⁵)₂,     SO₂R⁵, SO₂N(R⁵)₂, or Ar¹; -   each R⁵ is independently selected from R or Ar; -   V¹, V² and V³ are each independently selected from nitrogen or     C(R⁶); -   each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR,     SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂,     OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or     SO₂N(R⁴)₂; and -   each Ar¹ is independently selected from an optionally substituted     5–7 membered saturated, partially unsaturated, or fully unsaturated     monocyclic ring having 0–4 heteroatoms independently selected from     nitrogen, oxygen, or sulfur.

Preferred Ar groups of formula V are those set forth for compounds of formula I or Ib, supra.

Preferred V¹, V², and V³ groups of formula V are those set forth for compounds of formula I or Ib, supra.

Preferred R² groups of formula V are those set forth for compounds of formula I or Ib, supra.

Representative compounds of formula I are set forth in Table 1 below.

TABLE 1

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-1000

I-1001

I-1002

I-1003

I-1004

I-1005

I-1006

I-1007

I-1008

I-1009

I-1010

I-1011

I-1012

I-1013

I-1014

I-1015

I-1016

I-1017

I-1018

I-1019

I-1020

I-1021

I-1022

I-1023

I-1024

I-1025

I-1026

I-1027

I-1028

I-1029

I-1030

I-1031

I-1032

I-1033

I-1034

I-1035

I-1036

I-1037

I-1038

I-1039

I-1040

I-1041

I-1042

I-1043

I-1044

I-1045

I-1046

I-1047

I-1048

I-1049

I-1050

I-1051

I-1052

I-1053

I-1054

I-1055

I-1056

I-1057

I-1058

I-1059

I-1060

I-1061

I-1062

I-1063

I-1064

I-1065

I-1066

I-1067

I-1068

I-1069

I-1070

I-1071

The compounds of the present invention may be prepared as illustrated by the Schemes I–XVII below, by the Synthetic Examples described herein, and by general methods known to those of ordinary skill in the art.

Scheme I above shows a general method for preparing the aminoindazole compounds 3 where R¹ is other than hydrogen. When R¹ is an alkyl or aryl group, the nitro-indazole compound 2 may be prepared by methods substantially similar to those described by Henke, et al, J. Med. Chem., 1997, 40, 2706. The reduction of the nitro group at step (b) to afford compound 3 is achieved by the methods described by Bellamy, et al, Tetrahedron Lett., 1984, 25, 839. Alternatively, reduction of the nitro group of compound 2 can be achieved by treating 2 with hydrogen gas in the presence of Pd/C by methods substantially similar to those described by Boyer, et al, J. Chem. Res. Miniprint, 1990, 11, 2601. Another alternative method for achieving the reduction of the nitro group of compound 2 is by hydrolysis using a method substantially similar to that described by Lee, et al, Synthesis, 2001, 1, 81.

Scheme II above shows a general method for preparing the aminoindazole compounds 3 where R¹ is an amino or alkylamino group. The nitro-indazole compound 2 may be prepared from 2-fluoro-5-nitro-benzonitrile (1) by methods substantially similar to those describe by Parnell, et al, J. Chem. Soc., 1959, 2363. Amino-indazole compound 3 may then be prepared from compound 2 as described above for Scheme I.

Scheme III above shows a method for preparing compounds of formula I where R¹ is halogen. For example, 5-nitro-1H-indazole (5) may be chlorinated to afford 3-chloro-5-nitro-1H-indazole (6) using the methods described by v. Auwers, et al, Justus Liebigs Ann. Chem., 1927, 451, 295. Alternatively, the nitroindazole 5 can be treated with N-chlorosucciniimide to form a 3-chloro nitroindazole 6. The reduction of 6 to form the amino compound 7 may be achieved by following the methods described by Boyer, et al., J. Chem. Res. Miniprint, 1990, 11, 2601.

Scheme IV above outlines a synthetic route for preparing compounds of formula I. The starting aminoindazole 3 is coupled to a carboxylic acid compound 8 to form compounds of formula I using standard coupling conditions known in the art. Where necessary, reactive functional groups of R² may be protected before coupling. In certain cases, the yield of the coupling reaction has been improved by protecting the indazole ring NH, with a Boc group.

Scheme V above shows a general method for preparing α-hydroxy acids 12 used for preparing compounds of formula Ib, where R³ is OH, according to the methods described in Scheme IV. The formation of the α-hydroxy ester compound 11 front 9 and 10 was achieved by methods substantially similar to those described by Hernandez, et al, J. Org. Chem., 1995, 60, 2683. The oxaziridine reagent 10 can be prepared according to the procedure described by Davies, et al., J. Org. Chem., 1988, 53, 2087.

Scheme VI shows a general method for preparing compounds of formula Ib where R³ is a variety of amino groups from compounds of formula Ib where R³ is a hydroxy group as described above in Scheme V. Compound 13 may be treated with methanesulfonyl chloride and pyridine in THF to afford the mesyl derivative 14. The mesyl group may then be displaced by the desired amino group to afford compound 15. Removal of the Boc protecting group provides compound 16. Each of these steps are well known to one of skill in the art.

Scheme VII above shows a method for preparing carboxylic acid intermediates useful for preparing compounds of formula Ib where R³ is an amino group. This method may be used to prepare compounds of formula Ib where R³ is a variety of amino groups of formula N(R⁴)₂, N(R)COT_(n)N(R⁴)₂, or N(R)T_(n)N(R⁴)₂. Each of the above steps is well known to one of skill in the art. Carboxylic acid compound 20 may then be coupled to the amino-indazole according to Scheme IV to afford compounds of formula Ib.

Scheme VIII above shows the preparation of 3-iodo-5-nitroindazole (21) from 5-nitroindazole (5) according to methods substantially similar to that described in published PCT application number WO 02/10137.

Scheme IX above shows a method for the preparation of 3-bromo-5-nitroindazole, by a method substantially similar to that described by Benchidimi, et al, J Het. Chem., 1979, 16, 1599.

Scheme IX above shows a general method for the preparation of compounds of formula I where R¹ is an alkynyl group. The bromoindazole (22) is coupled with propyne (23), by the Sonograshira coupling method, to afford 5-nitro-3-prop-1-ynyl-1H-indazole (24). One of skill in the art would recognize that a variety of alkynes are amenable to the above reaction and are useful for the preparation of a variety of compounds of formula I wherein the T moiety of the R¹ group is an alkynyl group.

Scheme X above shows an alternative method for the preparation of nitroindazoles (2). The NH-group of the iodoindazole compound 21 may be protected. Although use of the MEM-protecting group is depicted above, one of skill in the art would recognize that a variety of protecting groups would be suitable for the above reaction. Other amino protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, 1991, published by John Wiley and Sons. The amino-protected iodoindazole (25) is coupled to a boronic acid using the Suzuki coupling methods that are well known in the art. One of ordinary skill in the art would recognize that a variety of boronic acids may be used in the Suzuki coupling thereby resulting in a variety of indazoles (26) where R¹ is alkyl or aryl.

Scheme XI above shows a general method for the preparation of 7-chloro-5-nitroindazole (28) by treating 2-chloro-6-methyl-4-nitro-phenylamine (27) with sodium nitrate in the presence of acetic acid.

Scheme XII above shows a general method for preparing compounds of formula I having an R⁶ substituent at the 7-position (31). At step (a), 2-bromo-6-methyl-4-nitro-phenylamine (29) is coupled with a boronic acid using Suzuki coupling conditions to form the intermediate compound (30). One of ordinary skill in the art would recognize that a variety of boronic acids are suitable for the above reaction and would be useful in preparing a variety of compounds of formula I having an R⁶ substituent at the 7-position of the indazole ring (31). The indazole ring is formed at step (b) by treating intermediate (30) with sodium nitrate and acetic acid at reflux.

Scheme XIV above shows a general method for preparing the protected amino acid intermediates (36) useful for preparing compounds of formula Ib where R³ is T_(n)N(R⁴)₂. The cyano compound (33) is prepared by treating the ester (17) with lithiumdiisopropylamide (LDA) at −78° C. then adding iodoacetonitrile. The nitrile is reduced using hydrogen in the presence of a platinum catalyst by a method substantially similar to that described by Prager, et al, Aust. J. Chem., 1997, 50, 813. The resulting amine (34) is hydrolyzed to form the acid compounds 35. The amino groups is then protected with a BOC group by treating 35 with BOC-anhydride in the presence of aqueous sodium carbonate in tetrahydrofuran. Other amino protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, 1991, published by John Wiley and Sons.

Scheme XV above shows an alternative method for preparing the protected amino acid intermediates (36) useful for preparing compounds of formula Ib where R³ is T_(n)N(R⁴)₂. Michael addition of tert-butylacrylate to the anion of ester 17 affords the diester 37. The tert-butyl ester of compound 37 is selectively cleaved to afford the acid intermediate 38. The mono-ester 38 is then treated sequentially with diphenylphosphorylazide and tert-butanol to afford the BOC-protected amino ester 39. Hydrolysis of ester affords the desired protected amino acid intermediate (36).

Scheme XVI above shows a general method for preparing compounds of the present invention where V³ is N. The pyridopyrazole intermediate 41, useful for the preparation of compounds of the present invention where V³ is N, is prepared from the amino protected pyridine compound 40 by methods substantially similar to those described by Foster, H. E. et. al., J. Chem. Soc., Perkin Trans 1, 1973, 2901.

Scheme XVI above shows a general method for preparing compounds of the present invention wherein a methylene unit of the T moiety of the R¹ group of formula I is replaced by either —O— or —S—. The formation of the indazole 42 was achieved by methods substantially similar to those described by Pfannstiel, K. et. al., Ber1942, 75B, 1096 and Vicente, J et al., Heterocycles, 1997, 45 (1), 129. Indazole 45 was synthesized from compound 42 following a procedure outlined by Kuroda, T et al in JP50130759.

Scheme XVIII above shows a general scheme for preparing compounds of formula I where V¹ is nitrogen by methods substantially similar to that described by Fanta, Org. Synth. Coll., 4, 844.

Scheme XVIII above shows a synthetic route for preparing compounds of the present invention where R¹ is NH₂, NHC(O)R, or NHC(O)Ar. Nitrile 4 may be treated with hydrazine to afford 3-aminoindazole 49. Selective Boc-protection of the endocyclic nitrogen, followed by acylation of the exocyclic nitrogen affords 5-nitroindazole 51. The nitro group may be reduced by hydrogenation (Scheme III) and the resulting amino group coupled with an acid 8 as in Scheme IV. Alternatively, hydrogenation of 5-nitroindazole 50 affords 3,5-diaminoindazole 52. Selective acylation with acid 8 yields the indazole 53, which may be elaborated as shown to provide indazole 54. All of the methods used are known to those skilled in the art.

The activity of a compound utilized in this invention as an inhibitor of AKT, PKA, PDK1, p70S6K, or ROCK kinase may be assayed in vitro, in vivo or in a cell line according to methods known in the art. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated AKT, PKA, PDK1, p70S6K, or ROCK. Alternate in vitro assays quantitate the ability of the inhibitor to bind to AKT, PKA, PDK1, p70S6K, or ROCK. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/AKT, inhibitor/PKA, inhibitor/PDK1, inhibitor/p70S6K, or inhibitor/ROCK complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where compounds are incubated with AKT, PKA, PDK1, p70S6K, or ROCK bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of AKT, PKA, PDK1, p70S6K, or ROCK kinase are set forth in the Examples below.

According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of this invention is such that is effective to measurably inhibit a protein kinase, particularly AKT, PKA, PDK1, p70S6K, or ROCK kinase, in a biological sample or in a patient. Preferably the composition of this invention is formulated for administration to a patient in need of such composition. Most preferably, the composition of this invention is formulated for oral administration to a patient.

The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The term “measurably inhibit”, as used herein means a measurable change in AKT, PKA, PDK1, p70S6K, or ROCK activity between a sample comprising said composition and a AKT, PKA, PDK1, p70S6K, or ROCK kinase and al equivalent sample comprising AKT, PKA, PDK1, p70S6K, or ROCK kinase in the absence of said composition.

A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a AKT, PKA, PDK1, p70S6K, or ROCK family kinase.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitonieally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01–100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”.

For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tarcolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalizine; neurotrophic factors Such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinisonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

According to another embodiment, the invention relates to a method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. Preferably, the method comprises the step of contacting said biological sample with a preferred compound of the present invention, as described herein supra.

The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of AKT, PKA, PDK1, p70S6K, or ROCK kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

Another aspect of this invention relates to a method for treating an AKT-, PKA-, PDK1-, p70S6K-, or ROCK-mediated disease in a patient, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition comprising said compound. According to a preferred embodiment, the invention relates to administering a compound of formula I′, or a pharmaceutically acceptable composition comprising said compound. A more preferred embodiment relates to administering a preferred compound of formula I′, as described herein supra, or a pharmaceutically acceptable composition comprising said compound.

According to another embodiment, the present invention relates to a method for treating an AKT-, PKA-, PDK1-, p70S6K-, or ROCK-mediated disease in a patient, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula IIa, IIb, or V, or a pharmaceutically acceptable composition comprising said compound. According to another embodiment, said method comprises administering to a patient in need thereof, a therapeutically effective amount of a preferred compound of formula IIa, IIb, or V, as described herein supra, or a pharmaceutically acceptable composition comprising said compound.

According to another embodiment, the present invention relates to a method for treating an AKT-, PKA-, PDK1-, p70S6K-, or ROCK-mediated disease in a patient, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula III or IV, or a pharmaceutically acceptable composition comprising said compound. According to another embodiment, said method comprises administering to a patient in need thereof, a therapeutically effective amount of a preferred compound of formula III, or IV, as described herein supra, or a pharmaceutically acceptable composition comprising said compound.

According to another embodiment, the invention provides a method for treating or lessening the severity of an AKT-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

The term “AKT-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which AKT is known to play a role. The term “AKT-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with an AKT inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, cardiovascular disorders, rheumatoid arthritis, and neurodegenerative disorders. Preferably, said cancer is selected from pancreatic, prostate, or ovarian cancer.

According to another embodiment, the invention provides a method for treating or lessening the severity of a PKA-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

The term “PKA-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which PKA is known to play a role. The term “PKA-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with a PKA inhibitor. PKA-mediated diseases or conditions include, but are not limited to, proliferative disorders and cancer. According to another embodiment, the invention provides a method for treating or lessening the severity of a PDK1-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

According to another embodiment, the invention provides a method for treating or lessening the severity of an PDK1-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

The term “PDK1-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which PDK1 is known to play a role. The term “PDK1-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with a PDK1 inhibitor. PDK1-mediated diseases or conditions include, but are not limited to, proliferative disorders, and cancer. Preferably, said cancer is selected from pancreatic, prostate, or ovarian cancer.

According to another embodiment, the invention provides a method for treating or lessening the severity of a p70S6K-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

The term “p70S6K-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which p70S6K is known to play a role. The term “p70S6K-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with a p70S6K inhibitor. p70S6K-mediated diseases or conditions include, but are not limited to, proliferative disorders, such as cancer and tuberous sclerosis.

According to another embodiment, the invention provides a method for treating or lessening the severity of a ROCK-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.

The term “ROCK-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which ROCK is known to play a role. The term “ROCK-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Such conditions include, without limitation, hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, arteriosclerosis, spasm, retinopathy, inflammatory disorders, autoimmune disorders, AIDS, and osteoporosis.

According to another embodiment, the present invention relates to a method for treating or lessening the severity of a disease or condition selected from a proliferative disorder, a cardiac disorder, an inflammatory disorder, an autoimmune disorder, a viral disease, or a bone disorder, wherein said method comprises the step of administering an effective amount of a compound of the present invention. Preferably, said method comprises the step of administering an effective amount of a preferred compound of the present invention.

According to a preferred embodiment, the present invention relates to a method for treating or lessening the severity of a disease or condition selected from cancer, rheumatoid arthritis, asthma, HIV, angina pectoris, peripheral circulation disorder, hypertension, arteriosclerosis, or osteoporosis.

Preferably, the present invention relates to a method for treating or lessening the severity of a cancer.

More preferably, the present invention relates to a method for treating or lessening the severity of a cancer selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid.

Most preferably, the present invention relates to a method for treating or lessening the severity of pancreatic, prostate, or ovarian cancer.

In an alternate embodiment, the methods of this invention that utilize compositions that do not contain an additional therapeutic agent, comprise the additional step of separately administering to said patient an additional therapeutic agent. When these additional therapeutic agents are administered separately they may be administered to the patient prior to, sequentially with or following administration of the compositions of this invention.

The compounds of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of this invention. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

As used herein, the term “R_(t)(min)” refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows:

-   -   Column: XTerra C8 column, 4.6×150 mm     -   Gradient: 0–100% acetonitrile+methanol 60:40 (20 mM Tris         phosphate)     -   Flow rate: 1.51 mL/minute     -   Detection: 225 nm.

Example 1

2-(3-Chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (I-6): To a solution of 5-aminoindazole (1 mmol), HOBt (1 mmol) and 3-chlorophenylacetic acid (1.1 mmol) in DMF (4 mL) was added N-methylmorpholine (1.1 mmol). After stirring for 10 minutes, EDC-HCl (1.1 mmol) was added and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100A column, gradient 10%–100% B (solvent A: 0.05% TFA in water; solvent B: CH₃CN) over 10 minutes at 25 mL/min] to afford compound I-6 (79 mg, 42%). ¹H NMR (400 MHz, DMSO-d6) δ 3.68 (2H, s), 7.12–7.73 (6H, m), 8.00 (1H, s), 8.11 (1H, s), 10.10 (1H, s), 12.97 (1H, bs); MS (ES+): m/e=(M+H) 286.

Example 2

We have prepared other compounds of formula I by methods substantially similar to those described in Example 1. The characterization data for these compounds is summarized in Table 2 below and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table 2 below wherein ¹H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 2 Characterization Data for Selected Compounds of Formula I Compound No I- M+1(obs) R_(t)(min) ¹H NMR 1 — 6.65 2.61–2.67(2H, m), 2.91–2.95(2H, m), 7.19(1H, m), 7.27–7.29(4H, m), 7.37 (1H, d), 7.46(1H, d), 8.00(1H, s), 8.11 (1H, s), 9.89(1H, s), 12.95(1H, brs). 2 320 7.90 3.8(2H, s), 7.3–7.7(6H, m), 8.0(1H, s), 8.2(1H, s), 10.3(1H, s), 13.0(1H, s) 3 295 6.90 3.4(3H, s), 3.5(2H, m), 6.7(2H, d), 7.2(2H, d), 7.4(2H, q), 8.1(1H, s), 8.2(1H, s), 10.1(1H, s), 13.0(1H, s). 4 286 7.17 3.85(2H, s), 7.29–7.49(6H, m), 8.00 (1H, s), 8.10(1H, s), 10.20(1H, s), 13.00(1H, brs). 5 286 7.48 3.66(2H, s), 7.36–7.49(6H, m), 8.00 (1H, s), 8.11(1H, s), 10.18(1H, s) 13.00(1H, brs). 7 268 6.25 3.61(2H, s), 6.75–6.81(2H, m), 7.05 (1H, t), 7.15(1H, m), 7.44–7.45(2H, m), 8.00(1H, s), 8.12(1H, s), 9.54(1H, s), 10.06(1H, s), 13.00(1H, brs). 8 268 5.75 4.54(2H, s), 6.63(1H, d), 6.76(2H, m), 7.09–7.13(1H, m), 7.40–7.49(2H, m), 8.00(1H, s), 8.12(1H, s), 10.12(1H, s), 13.00(1H, brs). 9 268 5.51 3.51(2H, s), 6.68(2H, d), 7.14(2H, d), 7.42–7.45(2H, m), 8.00(1H, s), 8.11 (1H, s), 9.26(1H, s), 10.06(1H, s), 12.96(1H, brs). 10 302 7.67 4.16(2H, s), 7.46–7.57(6H, m), 7.85 (1H, d), 7.94(1H, d), 7.99(1H, s), 8.11 (1H, s), 8.17(1H, d), 10.33(1H, s), 12.97(1H, brs). 11 302 7.76 3.83(2H, s), 7.46–7.54(5H, m), 7.85–90 (4H, m), 8.00(1H, s), 8.14(1H, s), 10.25(1H, s), 12.98(1H, brs). 12 352 8.39 3.7(2H, s), 7.3–7.6(4H, m), 7.7(2H, d), 8.0(1H, s), 8.2(1H, s), 10.3(1H, s), 13.0(1H, s). 13 344 8.10 3.7(2H, s), 6.8(1H, d), 6.9(2H, d), 7.0–7.5(8H, m), 8.0(1H, s), 8.1(1H, s), 10.1(1H, s), 13.0(1H, s). 14 358 8.14 3.7(2H, s), 5.1(2H, s), 6.9(1H, dt), 7.0(1H, d), 7.2–7.5(9H, m), 8.0(1H, s), 8.1(1H, s), 10.1(1H, s), 13.0(1H, s). 15 344 8.21 3.6(2H, s), 7.0(4H, d), 7.1(1H, t), 7.3–7.5 (6H, m), 8.0(1H, s), 8.2(1H, s), 10.2(1H, s), 13.0(1H, s). 16 321 7.99 3.69(2H, s), 7.34(1H, d), 7.40(1H, d), 7.48(1H, d), 7.55–7.62(2H, m), 8.00 (1H, s), 8.10(1H, s), 10.20(1H, s), 12.98(1H, s) 17 288 7.20 3.67(2H, s), 7.19(1H, m), 7.38–7.49 (4H, m), 8.00(1H, s), 8.10(1H, s), 10.18(1H, s), 12.98(1H, brs). 18 288 7.23 3.71(1H, s), 7.07–7.13(3H, m), 7.40 (1H, d), 7.48(1H, d), 8.00(1H, s), 8.10 (1H, s), 10.19(1H, s), 12.98(1H, brs). 19 304 7.57 3.68(2H, s), 7.36–7.42(3H, m), 7.47 (1H, d), 7.56(1H, m), 8.00(1H, s), 8.10(1H, s), 10.18(1 H, s), 12.98(1H, brs). 20 304 7.41 3.7(2H, s), 7.3(1H, m), 7.4–7.6(4H, m), 8.0(1H, s), 8.2(1H, s), 10.2(1H, s), 13.1(1H, s) 21 296 6.67 3.6(2H, s), 6.0(2H, s), 6.7–6.9(3H, m), 7.4–7.5(2H, m), 8.0(1H, s), 8.2 (1H, s), 10.2(1H, s), 13.0(1H, bs) 22 356, 354 8.13 3.5(2H, s), 7.3–7.5(2H, q), 7.7(2H, dd), 7.8(1H, s), 8.0(1H, s), 8.2(1H, s), 10.4(1H, s), 13.0(1H, s). 23 253 5.40 3.71(2H, s), 7.36–7.49(3H, m), 7.75 (1H, m), 8.00(1H, s), 8.10(1H, s), 8.46 (1H, m), 8.54(1H, s), 10.23(1H, s), 12.98(1H, brs). 24 291 6.88 3.74(2H, s), 6.98(1H, t), 7.07(1H, t), 7.27(1H, s), 7.35(1H, d), 7.44–7.46 (2H, m), 7.63(1H, d), 8.00(1H, s), 8.12(1H, s), 10.10(1H, s), 10.91(1H, brs), 12.98(1H, brs). 25 308 7.90 3.94(2H, s), 7.38–7.47(4H, m), 7.61 (1H, s), 7.92(1H, d), 7.99(2H, m), 8.12(1H, s), 10.29(1H, s), 12.97(1H, brs). 26 258 6.67 3.66(2H, s), 7.11(1H, m), 7.33(1H, s), 7.42–7.50(3H, m), 8.00(1H, s), 8.12 (1H, s), 10.13(1H, s), 12.97(1H, brs). 27 258 7.90 3.87(2H, s), 6.98(2H, m), 7.39–7.42 (2H, m), 7.48(1H, m), 8.01(1H, s), 8.12(1H, s), 10.20(1H, s), 12.98(1H, brs). 28 244 7.49 1.16–1.23(2H, m), 1.51–1.61(4H, m), 1.74–1.76(2H, m), 2.23–2.31(3H, m), 7.39(1H, d), 7.45(1H, d), 7.99(1H, s), 8.12(1H, s), 9.83(1H, s), 12.98(1H, brs). 29 258 8.00 0.96–1.02(2H, m), 1.12–1.24(3H, m), 1.60–1.78(6H, m), 2.18(2H, m), 7.38 (1H, d), 7.45(1H, d), 7.99(1H, s), 8.12 (1H, s), 9.83(1H, s), 12.95(1H, brs). 30 272 8.47 1.18–1.26(2H, m), 1.39–1.72(12H, m), 2.01(1H, m), 2.22(2H, d), 7.39(1H, d), 7.45(1H, d), 7.99(1H, s), 8.13 (1H, s), 9.84(1H, s), 12.97(1H, brs). 31 268 6.02 5.11(1H, m), 6.41(1H, m), 7.29(1H, m), 7.34–7.38(2H, m), 7.45–7.58(4H, m), 8.00(1H, s), 8.15(1H, s), 9.93(1H, s), 12.97(1H, brs). 32 268 6.02 5.11(1H, m), 6.41(1H, m), 7.29(1H, m), 7.34–7.38(2H, m), 7.45–7.58(4H, m), 8.00(1H, s), 8.15(1H, s), 9.93(1H, s), 12.97(1H, brs). 33 310 6.93 2.17(3H, s), 6.00(1H, s), 7.38–7.49 (5H, m), 7.57(2H, m), 8.00(1H, s), 8.07(1H, s), 10.33(1H, s), 12.99(1H, brs). 34 286 6.29 5.12(1H, m), 6.47(1H, m), 7.19(2H, t), 7.45(1H, d), 7.54–7.58(3H, m), 8.00 (1H, s), 8.14(1H, s), 9.95(1H, s), 12.97(1H, brs). 35 302 6.95 5.14(1H, m), 6.52(1H, m), 7.42–7.47 (3H, m), 7.54–7.56(3H, m), 8.00(1H, s), 8.14(1H, s), 9.56(1H, s), 12.98 (1H, brs). 36 336 7.46 5.24(1H, m), 6.67(1H, m), 7.46(1H, d), 7.55(1H, d), 7.72–7.75(4H, m), 8.00(1H, s), 8.14(1H, s), 10.03(1H, s), 12.98(1H, brs). 37 347 7.07 5.11(1H, m), 6.52(1H, m), 7.44–7.57 (6H, m), 8.00(1H, s), 8.13(1H, s), 9.96 (1H, s), 12.98(1H, brs). 38 298 5.97 3.73(3H, s), 5.04(1H, m), 6.29(1H, m), 7.42–7.46(3H, m), 7.54(1H, m), 8.00 *1H, s), 8.15(1H, s), 9.88(1H, s), 12.98(1H, brs). 39 302 6.33 5.48(1H, m), 6.64(1H, m), 7.33–7.37 (2H, m), 7.44–7.48(2H, m), 7.57–7.60 (2H, m), 8.00(1H, s), 8.16(1H, s), 10.05(1H, s), 12.99(1H, brs). 40 302 6.91 5.15(1H, d), 6.59(1H, d), 7.35–7.56 (6H, m), 7.94(1H, s), 8.00(1H, s), 9.86 (1H, s), 12.98(1H, s) 41 314 4.99 3.73(3H, s), 4.95(1H, m), 6.20(1H, m), 6.88(2H, m), 6.94(1H, s), 7.45 (1H, d), 7.55(1H, d), 8.00(1H, s), 8.15 (1H, s), 8.95(1H, s), 9.83(1H, s), 12.97(1H, brs). 42 304 6.72 5.15(1H, m), 6.62(1H, m), 7.38–7.47 (3H, m), 7.53–7.55(2H, m), 8.00(1H, s), 8.13(1H, S), 9.97(1H, S), 12.98 (1H, S). 43 304 6.78 5.18(1H, m), 6.71(1H, m), 7.17–7.25 (3H, m), 7.46(1H, d), 7.54(1H, d), 8.00(1H, s), 8.13(1H, s), 9.99(1H, s), 12.99(1H, brs). 44 307 5.85 5.35(1H, d), 6.07(1H, d), 7.01–7.08 (1H, m), 7.10–7.18(1H, m), 7.36(3H, m), 7.46(1H, d), 7.58(1H, d), 7.75 (1H, d), 8.00(1H, s), 8.18(1H, s), 9.94 (1H, s), 11.01(1H, d), 12.96(1H, s). 45 318 7.15 5.30(1H, d), 6.58(1H, d), 7.44–7.59 (4H, m), 7.69(1H, d), 7.89–7.93(2H, m), 7.99(1H, s), 8.04(1H, s), 8.16(1H, s), 10.01(1H, s), 12.97(1H, s). 46 367 8.14 1.40(9H, s), 5.37(1H, m), 7.28–7.40 (4H, m), 7.46–7.52(4H, m), 8.00(1H, s), 8.09(1H, s), 10.25(1H, s), 12.98 (1H, brs). 47 367 8.14 1.40(9H, s), 5.37(1H, m), 7.28–7.40 (4H, m), 7.46–7.52(4H, m), 8.00(1H, s), 8.09(1H, s), 10.25(1H, s), 12.98 (1H, brs). 48 267 5.80 5.07(1H, brs), 7.37(1H, d), 7.44–7.53 (4H, m), 7.60(2H, m), 8.05(1H, s), 8.09(1H, s), 8.73(3H, brs), 10.58(1H, s), 13.06(1H, brs). TFA salt 49 267 5.80 5.07(1H, brs), 7.37(1H, d), 7.44–7.53 (4H, m), 7.60(2H, m), 8.05(1H, s), 8.09(1H, s), 8.73(3H, brs), 10.58(1H, s), 13.06(1H, brs). TFA salt 50 301 6.71 5.1(1H, s), 7.35(1H, d), 7.45–7.65 (5H, m), 8.10(2H, d), 8.8(3H, bs), 10.6(1H, bs), 13.1(1H, bs) TFA salt 51 301 6.69 5.13(1H, s), 7.36(1H, d), 7.51–7.55 (4H, m), 7.56(1H, s), 7.72(1H, s), 8.06–8.13 (1H, m), 8.78(3H, brs), 10.62 (1H, s), 13.08(1H, s) TFA salt 52 347 6.78 3.61(2H, brs), 4.60(1H, s), 7.30(2H, m), 7.41(4H, br m), 7.60(1H, s), 7.96 (1H, s), 8.09(1H, s), 8.16(1H, s), 10.11 (1H, brs,), 12.95(1H, s). TFA salt 53 335 7.19 3.10(2H, brs), 4.68(1H, s), 7.44(2H, m), 7.59(2H, br m), 7.75(1H, m), 7.88 (1H, s), 8.00(1H, s), 8.16(1H, s), 10.18 (1H, brs,), 12.99(1H, s). TFA salt 54 335 7.39 5.16(1H, s), 7.36(1H, d), 7.51–7.58 (2H, m), 7.81(1H, d), 7.88(1H, s), 8.06 (2H, m), 8.78(3H, brs), 10.60(1H, s), 13.08(1H, brs) TFA salt 55 319 6.93 5.19(1H, s), 7.37(1H, d), 7.51–7.61 (3H, m), 7.85(1H, m), 8.06–8.10 (2H, m), 8.83(3H, brs), 10.60(1H, s), 13.15(1H, brs) TFA salt 56 M−H 304 5.54 — 57 279 6.70 .7(2H, AB quartet), 5.6(1H, s), 7.4–7.7 (6H, m), 8.10(2H, s), 9.5(1H, bs), 10.2 (1H, bs), 11.05(1H, s), 13.1(0.5H, bs) TFA salt 58 317 6.93 5.30(1H, d), 7.40–7.45(1H, m), 7.50–7.55 (1H, m), 7.60–7.65(2H, m), 7.69 (1H, m), 7.89–7.93(2H, m), 7.99(2H, s), 8.05–8.1(2H, m), 8.95(2H, s), 10.75 (1H, s), 13.0(1H, brs). TFA salt 76 316 7.22 2.42(3H, s), 5.14(1H, m), 6.57(1H, m), 7.37–7.40(3H, m), 7.48–7.53(2H, m), 7.59(1H, s), 8.07(1H, s), 9.95(1H, s), 12.55(1H, brs). 77 333 7.17 2.45(3H, s), 5.15(1H, brs), 7.37(1H, d), 7.44(1H, d), 7.61(2H, m) 7.84 (1H, d), 7.95(1H, s), 8.76(3H, brs), 10.58(1H, s), 12.66(1H, s) TFA salt 78 336 7.80 5.16(1H, d), 6.63(1H, d), 7.40(2H, m), 7.50(2H, m), 7.56(1H, s), 7.67(1H, m), 8.14(1H, s), 10.14(1H, s), 13.23(1H, s) 79 330 7.55 1.28(3H, t), 2.85(2H, q), 5.14(1H, d), 6.58(1H, d), 7.35–7.42(3H, m), 7.48–7.52 (2H, m), 7.59(1H, s), 8.11(1H, s), 9.95(1H, s), 12.55(1H, s). 80 344 7.91 1.33(6H, d), 3.25(1H, sep), 5.14(1H, d), 6.59(1H, d), 7.37–7.42(3H, m), 7.49(1H, d), 7.54–7.59(2H, m), 8.17 (1H, s), 9.95(1H, s), 12.51(1H, s). 81 378 8.30 5.15(1H, d), 6.63(1H, d), 7.36–7.42 (3H, m), 7.52–7.54(4H, m), 7.60(1H, s), 7.73(1H, d), 7.91(2H, d), 8.52(1H, s), 10.09(1H, s), 13.19(1H, s). 82 301 6.87 3.65(2H, s), 5.25(2H, brs), 7.16(1H, d), 7.26(1H, d), 7.32–7.37(3H, m), 7.43(1H, s), 7.94(1H, s), 10.05(1H, s), 11.29(!H, brs). 83 336 7.54 3.66(2H, s), 5.24(2H, brs), 7.15(1H, d), 7.25(1H, d), 7.33(1H, m), 7.59–7.61 (2H, m), 7.94(1H, s), 10.06(1H, s)<11.29(1H, brs). 84 282 6.15 3.56–3.58(1H, m), 3.82–3.86(1H, m), 4.07–4.09(1H, m), 4.96(1H, m), 7.25 (1H, m), 7.31–7.35(2H, m), 7.39–7.47 (4H, m), 7.99(1H, s), 8.16(1H, s), 10.10(1H, s), 12.95(1H, brs). 85 336, 334 7.13 3.6(1H, m), 3.87(1H, m), 4.00(1H, m), 5.01(1H, bs), 7.35–7.4(3H, m), 7.47(1H, d), 7.6(1H, d), 8.0(1H, s), 8.15(1H, s), 10.18(1H, s) 86 266 7.23 1.4(3H, d), 3.8(1H, q), 7.2–7.5(7H, m), 8.0(1H, s), 8.2(1H, s), 10.1(1H, s), 13.0(1H, s) 87 370 8.07 1.5(3H, d), 3.9(1H, q), 7.3–7.7(10H, m), 7.8(1H, s), 8.0(1H, s), 8.2(1H, s), 10.2(1H, s), 13.0(1H, s). 88 320 8.68 0.8–1.9(9H, m), 2.6(1H, m), 7.2–7.5 (7H, m), 8.0(1H, s), 8.2(1H, s), 10.1 (1H, s), 13.0(1H, s) 89 328 8.29 5.1(1H, s), 7.2–7.5(12H, m), 8.0(1H, s), 8.2(1H, s), 10.4(1H, s), 13.1(1H, s) 90 292 6.09 2.9(2H, d), 4.45(1H, t), 7.4–7.5(3H, m), 7.7–7.8(3H, m), 8.0(1H, s), 8.1 (1H, d), 10.6(1H, s), 13.0(1H, s). 91 317 7.7 2.7(2H, t), 4.3(2H, t), 7.0(2H, d), 7.3–7.5 (4H, m), 8.0(1H, s), 8.2(1H, s), 10.1(1H, s), 13.0(1H, s). 92 280 7.5 1.87(2H, q), 2.3(2H, t), 2.6(2H, t), 7.1–7.3(5H, m), 7.4–7.5(2H, q), 8.0 (1H, s), 8.1(1H, s), 9.9(1H, s), 13.0 (1H, s). 93 304 7.45 3.7(2H, s), 7.2(1H, t), 7.3–7.6(4H, m), 8.0(1H, s), 8.1(1H, s), 10.3(1H, s), 13.0(1H, s). 94 362, 360 7.68 3.6(2H, s), 3.8(3H, s), 7.0(1H, t), 7.4–7.5 (4H, m), 8.0(1H, s), 8.1(1H, s), 10.1(1H, s), 13.0(1H, s). 95 351, 349 7.46 3.07(2H, m), 3.21(2H, m), 4.15(1H, m), 7.26(1H, d, J=8.0Hz), 7.34(1H, d, J=8.7Hz), 7.53(2H, m), 7.60(1H, m), 8.06(2H, d, J=7.45Hz), 8.30(3H, brs), 10.46(1H, s), 13.09(1H, s) TFA salt 96 351, 349 7.46 3.08(2H, m), 3.21(2H, m), 4.16(1H, m), 7.26(1H, d, J=8.4Hz), 7.35(1H, d, J=8.5Hz), 7.50(2H, m), 7.69(1H, m), 8.06(2H, d, J=6.6Hz), 8.25(3H, brs), 10.46(1H, s), 13.09(1H, s). TFA salt

Example 3

5-[2-(3-Chloro-phenyl)-2-methanesulfonyloxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester: 5-Amino-indazole-1-carboxylic acid tert-butyl ester was prepared following the procedure outlined by S. J. Brickner, WO9002744. 5-Amino-indazole-1-carboxylic acid tert-butyl ester was then coupled with 2-(3-chlorophenyl)-2-hydroxyacetic acid following the procedure as described in Example 1 to afford 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester. To a solution of 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (7.47 mmol) in dry THF (20 mL) at 0° C. was added pyridine (37.33 mmol, 5 equivalents) followed by methanesulfonyl chloride (22.40 mmol, 3 equivalents) added in a dropwise fashion. The resultant solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (3.58 g, qunatitative yield), which was used without further purification.

Example 4

5-[2-(2-tert-Butoxycarbonylamino-ethylamino)-2-(3-chloro-phenyl)-acetylamino]-indazole-1-carboxylic acid tert-butyl ester: To a solution of 5-[2-(3-chloro-phenyl)-2-methanesulfonyloxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (1.49 mmol) in dry THF (4 mL) was added pyridine (4.48 mmol, 3 equivalents) followed by followed by a dry THF solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (3 equivalents, ˜0.5 mL/mmol). The resulting solution was refluxed at 60° C. overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using eluting with EtOAc:hexane (60:40) to afford the title compound in 85% yield.

Example 5

2-(2-Amino-ethylamino)-2-(3-chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (I-59): To 5-[2-(2-tert-butoxycarbonylamino-ethylamino)-2-(3-chloro-phenyl)-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (1.26 mmol) was added trifluoroacetic acid (5 mL) and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Delta Pak C18, 15 uM, 100A column, gradient 10%–100% B (solvent A: 0.05% TFA in water; solvent B: CH₃CN) over 10 minutes at 25 mL/min] to afford compound the title compound (172 mg, 82%). ¹H NMR (400 MHz, DMSO-d6) δ 2.5–5.5(9H, br m), 6.9–7.3(1H, m), 7.4–8.2(8H, m), 9.2–10.8(1H, br m), 13.0(1H, br s); MS (ES+): m/e=344.4(100%), 346.4(40%)

Example 6

We have prepared other compounds of formula I by methods substantially similar to those described in Examples 1, 3, 4, and 5. The characterization data for these compounds is summarized in Table 3 below and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table 3 below wherein ¹H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 3 Characterization Data for Selected Compounds of Formula I M+1 Compound No (obs) R_(t)(min) ¹H NMR 60 — 6.0 2.0(2H, m), 2.8–3.2(4H, m), 5.2(1H, brs), 7.4(1H, m), 7.6(4H, m), 7.8(4H, m), 8.1(1H, m), 9.6–9.8(2H, brs), 10.8(1H, brs), 12.9–13.3(1H, brs) TFA salt 61 358 5.8 2.6–2.7(3H, s), 2.9–3.4(4H, m), 5.1(1H, brs), 7.4(1H, m), 7.5–7.6 (4H, m), 7.7(1H, s), 8.1(2H, m), 10.5–10.7(1H, brs), 12.7–13.3(1H, brs) TFA salt 62 372.5 6.1 2.8–3.4(10H, m), 4.7–4.9(1H, brs), 7.3–7.7(6H, m), 8.0–8.2(2H, m), 10.2–10.5(1H, brs), 12.7–13.3(1H, brs) TFA salt 63 372 6.0 1.2(3H, m), 2.8–3.3(6H, m), 5.0(1H, brs), 7.4(1H, m), 7.6(4H, m), 7.7(1H, s), 8.0–8.1(2H, m), 10.5–10.8(1H, brs), 12.8–13.3(1H, brs) TFA salt 64 434 7.5 2.8–3.4(4H, m), 4.2–4.3(2H, s), 4.7–5.1(1H, brs), 7.3–7.6(10H, m), 7.7(1H, s), 8.1(2H, m), 10.4–10.6 (1H, brs), 12.9–13.1(1H, brs) TFA salt 65 392 7.6 4.2–4.4(2H, m), 5.2(1H, s), 7.3(1H, m), 7.4–7.6(6H, m), 7.7(1H, m), 7.9(1H, m), 8.0–8.1(2H, m), 8.7(1H, m), 9.6–10.5(1H, brs), 10.6(1H, s), 12.9–13.2(1H, brs) TFA salt 66 406 7.7 3.2(3H, brs), 3.4(1H, brs), 5.2(1H, s), 7.5(3H, m), 7.6(4H, m), 7.8(2H, m), 8.1(2H, m), 8.6(1H, s), 9.6–9.9 (1H, brs), 10.7(1H, s), 12.8–13.2 (1H, brs) TFA salt 67 372 6.0 3.2(3H, brs), 3.4(1H, brs), 5.2(1H, s), 7.5(3H, m), 7.6(4H, m), 7.8(2H, m), 8.1(2H, m), 8.6(1H, s), 9.6–9.9 (1H, brs), 10.7(1H, s), 12.8–13.2 (1H, brs) TFA salt 68 400 6.6 0.9–1.0(3H, m), 1.5–1.6(2H, m), 2.0(2H, m), 2.7–3.1(6H, m), 5.2(1H, brs), 7.4(1H, m), 7.6(5H, m), 7.7–7.8 (1H, m), 8.1(2H, m), 8.4–8.6(2H, brs), 9.7–9.9(1H, brs), 12.9–13.1 (1H, brs) TFA salt

Example 7

({[(3-Chloro-phenyl)-(1H-indazol-5-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester: To a solution of 2-amino-2-(3-chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (0.17 mmol) and tert-butoxycarbonylamino-acetic acid (0.17 mmol) in THF (2 mL) was added HOBt (0.18 mmol). The reaction mixture was cooled to 0° C. and EDC (0.18 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was then concentrated in vacuo and the residue was was partitioned between EtOAc and brine. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc:hexanes (80:20) to give the title compound in 55% yield.

Example 8

2-(2-Amino-acetylamino)-2-(3-chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (I-74): To a solution of ({[(3-chloro-phenyl)-(1H-indazol-5-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (0.09 mmol) in dichloromethane (2.5 mL) at 0° C. was added trifluoroacetic acid (2.5 mL) and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to afford compound the title compound (9 mg, 24%). ¹H NMR (400 MHz, DMSO-d6) δ 3.8(2H, m), 5.8(1H, m), 7.4–7.7(5H, m), 7.9–8.2(4H, m), 9.3–9.4(1H, m), 10.6 (1H, s), 13.0(1H, br s); MS (ES+): m/e=358.3(40%), 134.3(100%).

Example 9

We have prepared other compounds of formula I by methods substantially similar to those described in Examples 7 and 8. The characterization data for these compounds is summarized in Table 4 below and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table 4 below wherein ¹H NMR data was obtained in at 400 MHz deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 4 Characterization Data for Selected Compounds of Formula I Compound No I- M+1(obs) R_(t)(min) ¹H NMR 75 344, 346 7.22 2.3–2.4(2H, m), 2.8(2H, m), 3.7(1H, s), 7.3–7.6(6H, m), 8.0– 8.2(2H, m), 8.8–9.0(1H, brs), 10.4(1H, m), 12.8–13.0(1H, brs)

Example 10

(2-tert-Butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid methyl ester: To a solution of (3-methoxy-phenyl)-acetic acid methyl ester (19.6 mmol) in CCl₄ was added N-bromosuccinimide (19.6 mmol) and the reaction mixture was irradiated for 2 hours. The reaction mixture was then concentrated in vacuo to afford the intermediate bromo-(3-methoxy-phenyl)-acetic acid methyl ester. To a solution of bromo-(3-methoxy-phenyl)-acetic acid methyl ester in THF (30 mL) under an atmosphere of nitrogen was added a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (20.6 mmol) in THF (20 mL) followed by K₂CO₃ (39.2 mmol, 2 equivalents). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (2×50 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo to afford an oil. The oil was purified by silica gel column chromatography using as eluent EtOAc:petrol (1:1) to give the title compound as an oil in 53% yield.

Example 11

(2-tert-Butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid: To a solution of (2-tert-butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid methyl ester (10.4 mmol) in TiAF:H₂O (3:1, 40 mL) was added LiOH (10.9 mmol) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo then diluted with H₂0 and neutralised with 2M HCl solution and the resulting precipitate was collected by filtration to afford the title compound in 46% yield.

Example 12

2-(2-Amino-ethylamino)-N-(1H-indazol-5-yl)-2-(3-methoxy-phenyl)-acetamide (I-1017): 5-Aminoindazole was coupled with (2-tert-butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid according to the method described in Example 1. The BOC protecting group was then removed according to the method described in Example 8 to afford compound I-1017. ¹H NMR (400 MHz, DMSO-d6) δ 3.02–3.14 (4H, m), 3.80 (3H,s), 4–5 (1H, vbr s), 5.11 (1H, brs), 7.05 (1H,d), 7.20 (2H,m), 7.40 (2H,m), 7.52 (1H,d), 7.5–8 (2H, brs), 8.05 (1H,s), 8.07 (1H,s), 8.2–10.1 (1H, brs), 10.68 (1H,brs), 13.15 (1H,brs); MS (ES+): m/e=340.

Example 13

5-Nitro-1H-indazole-3-ylamine: Hydrazine monohydrate (17.5 mL, 362 mmol) was added to a hot (50° C.) solution of 2-fluoro-5-nitrobenzonitrile (30 g, 181 mmol) in EtOH (500 mL). The mixture was heated at reflux for 4 hours then allowed to cool to room temperature, whereupon the product precipitated from solution. The filtrate was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The organic phase was separated, dried over magnesium sulfate and concentrated to obtain further product. The combined product (32.2 g, quant.) was taken on to the following step without further purification.

Example 14

3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester: Dimethylaminopyridine (4 g, 36 mmol) was added to a solution of 5-nitro-1H-indazol-3-ylamine (32.2 g, 181 mmol), tert-butyldicarbonate (39.4 g, 181 mmol) and triethylamine (25 mL, 181 mmol) in THF (1 L) at room temperature under nitrogen. After stirring for 30 minutes, the reaction mixture was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase washed with brine, dried (MgSO₄), and concentrated to an orange solid. Recrystallisation from ethyl acetate provided the title product as a yellow solid (25 g, 50%). ¹H NMR (400 MHz, DMSO) 1.60 (9H, s), 6.75 (2H, brs), 8.10 (1H, d), 8.36 (1H, d), 8.96 (1H, s); MS (ES−) m/e=277.

Example 15

3,5-Diamino-indazole-1-carboxylic acid tert-butyl ester: 3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester (3 g, 10.8 mmol) was dissolved in MeOH (50 mL) and the solution degassed (3× alternating vacuum/nitrogen purges). Palladium on charcoal 10% w/w (300 mg) was added and the nitrogen atmosphere replace by hydrogen. After 3 hours, the mixture was filtered through a pad of Celite® and the filtrate concentrated to afford the title compound as a highly viscous oil (2.17 g, 81%). ¹H NMR (400 MHz, DMSO)1.55 (9H, s), 5.07 (2H, brs), 6.04 (2H, brs), 6.79–6.82 (2H, m), 7.62 (1H, brs). MS (ES+) m/e=249.

Example 16

3-Amino-5-[4-tert-butoxycarbonylamino-2-(3,4-dichloro-phenyl)-butyrylamino]-indazole-1-carboxylic acid tert-butyl ester: To a stirred solution of 3,5-diamino-indazole-1-carboxylic acid tert-butylester (2.17 g, 8.75 mmol), PyBroP (4.1 g, 8.75 mmol) and 4-tert-butoxycarbonylamino-2-(3,4-dichloro-phenyl)-butyric acid (3 g, 8.75 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (3.0 mL, 17.5 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature over 4 hours then was concentrated and the residue partitioned between EtOAc and ammonium chloride (saturated, aqueous). The organic phase was separated and washed with sodium bicarbonate (saturated, aqueous), then dried (sodium sulfate) and concentrated to a brown foam. Purification by column chromatography (silica, 20% petroleum ether-EtOAc gave the title compound as a light brown solid (2.92 g, 58%); ¹H NMR (400 MHz, DMSO) 1.36 (9H, s), 1.56 (9H, s), 1.80–1.90 (1H, m), 2.10–2.20 (1H, m), 2.89 (2H, m), 6.29 (2H, brs), 6.87 (1H, t), 7.38 (1H, d), 7.45 (1H, d), 7.61–7.65 (2H, m), 7.90 (1H, m), 8.19 (1H, s), 10.30 (1H, s); MS (ES+) m/e=578.

Example 17

3-(3-Chlorobenzoylamino)-5-nitroindazole-1-carboxylic acid tert-butyl ester: 3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester (600 mg, 2 mmol) was dissolved in dry pyridine (15 mL) under nitrogen. The solution was cooled on an ice bath and 3-chlorobenzoyl chloride (0.3 mL, 2 mmol) added. After 6 hours, the mixture was diluted with EtOAc, washed with 1M hydrochloric acid solution (×3) and brine then dried over magnesium sulfate and concentrated to a solid. Purification by column chromatography (silica, 7:3 petrol)-EtOAc) afforded the title compound as a solid (300 mg, 39%); ¹H NMR (400 MHz, CDCl₃) 1.77 (9H, s), 7.52 (1H, t), 7.62 (1H, d), 7.90 (1H, d), 8.07 (1H, m), 8.32 (1H, d), 8.45 (1H, d), 9.22 (1H, brs), 9.32 (1H, s); MS (ES+) m/e=417.

Example 18

(5-Nitro-1H-indazol-3-yl)-phenylamine: 2-Fluoro-5-nitro-N-phenyl benzamide (100 mg, 0.38 mmol) was suspended in EtOH (10 mL) and the mixture heated to 50° C. To the resulting solution was added hydrazine monohydrate (0.1 mL, 1.9 mmol). The mixture was heated at reflux for 30 minutes, at which time LC-MS showed complete conversion to the aryl hydrazine (ES+m/e=273). The mixture was allowed to cool to room temperature, concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase was dried over sodium sulfate and concentrated to a yellow foam. The residue was dissolved in phosphorous oxychloride (5 mL) and the mixture heated at 90° C. for 30 minutes, then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated to afford the title compound as a red solid (80 mg, 83%); ¹H NMR (400 MHz, DMSO) 6.88 (1H, t), 7.31 (2H, t), 7.51 (1H, d), 7.74 (2H, t), 8.17 (1H, dd), 9.24 (1H, s), 9.42 (1H, s), 12.74 (1H, s); MS (ES+) m/e=255.

Example 19

N-(3-Cyano-phenyl)-2-fluoro-5-nitro-thiobenzamide: To a solution of N-(3-Cyano-phenyl)-2-fluoro-5-nitro-benzamide (10.0 g; 0.035 mol) in toluene (100 mL) was added Lawson's reagent (7.84 g; 0.019 mol) and the solution refluxed for 16 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography, eluting with 30% ethyl actetate/petroleum ether to afford the title compound as a yellow solid (8.56 g; 81%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.60–7.75 (2H, m), 7.80 (1H, m), 8.15 (1H, d), 8.40–8.50 (1H, m), 8.50 (1H, s), 8.50–8.55 (1H, n), 12.45 (1H, br). Mass Spectrum (ES−) m/e=300.22.

Example 20

3-(5-Nitro-1H-indazol-3-ylamino)-benzonitrile: To a solution of N-(3-Cyano-phenyl)-2-fluoro-5-nitro-thiobenzamide (8.56 g; 0.028 mol) in n-butanol (300 mL) was added hydrazine hydrate (2.54 mL; 0.053 mol) and the solution refluxed for 3 hours. The reaction mixture was concentrated in vacuo and triturated with hot ethanol to afford the title compound as a red solid (4.93 g; 62%). ¹H NMR (400 MHz, DMSO-d6) δ_(H) 7.30 (1H, d), 7.45–7.60 (2H, m), 7.90 (1H, d), 8.20 (1H, d), 8.25 (1H, s), 9.20 (1H, s), 9.85 (1H, s). Mass Spectrum (ES−) m/e=278.28.

Example 21

3-Chloro-5-nitroindazole: 5-Nitroindazole (5 g, 30.7 mmol) was suspended in glacial AcOH (150 mL) and the mixture heated to 50° C. N-Chlorosuccinimide (4.9 g, 36.8 mmol) was added and the mixture heated at relux (solution forms) for 1 hour. The reaction mixture was concentrated and partitioned between EtOAc and brine. The organic phase was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated to a yellow solid. Recrystallisation from EtOH provided the title compound as a pale yellow solid (2.63 g, 43%); ¹H NMR (400 MHz, DMSO) δ 7.73 (1H, d), 8.21 (1H, dd), 8.51 (1H, d), 13.97 (1H, brs); MS (ES−) m/e=196.

Example 22

3-Bromo-5-nitroindazole: 5-Nitroindazole (10 g, 61.3 mmol) was dissolved in acetic acid (170 mL) and the mixture heated to 80° C. Bromine (3.1 mL, 60.7 mmol) was added slowly and the mixture heated to reflux. After 2 hours, the reaction mixture was allowed to cool to room temperature, and the resulting precipitate filtered off. Additional product was isolated by concentrating the filtrate, partitioning the residue between chloroform and saturated sodium bicarbonate solution, separating and drying the organic phase over sodium sulfate. Concentration gave a solid which was combined with the original precipitate to give the title compound as a yellow solid (11.4 g, 77%). ¹H NMR δ 7.74 (1H, d), 8.21 (1H, dd), 8.40 (1H, d), 14.06 (1H, brs); MS (ES−) m/e=240.

Example 23

3-iodo-5-nitro-1H-indazole: To a solution of 5-nitro-1H-indazole (10.0 g, 62.3 mmol) in DMF (120 ml) was added potassium hydroxide (12.9 g, 230.4 mmol) followed by iodine (31.1 g, 122.6 mmol) portion wise over 5 minutes. The resulting mixture was stirred at room temperature for 14 hours and then poured onto 10% sodium metabisulfite (100 ml) and extracted into ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na₂SO₄) and concentrated in vacuo to afford the title compounds as a pale orange solid (17.5 g). ¹H NMR (400 MHz, DMSO-d6) δ 7.77 (1H, d), 8.26 (1H, d), 8.34 (1H, s), 14.15 (1H, s). MS (ES+) m/e=290.

Example 24

5-Nitro-3-(trimethylsilylethynyl)-indazole-1 carboxylic acid tert-butyl ester: 3-Bromo 5-nitro-indazole-1-carboxylic acid tert-butyl ester (2 g, 5.8 mmol) was dissolved in dry DMF (30 mL) under nitrogen and triethylamine (1.6 mL, 1.6 mmol) added. Copper iodide (20 mg, 0.12 mmol), trimethylsilylacetylene (2.5 mL, 17.4 mmol) palladium bis-triphenylphosphine dichloride (84 mg, 0.12 mmol) and a further 1.6 mL of triethylamine were added and the mixture heated at 50° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was taken up in EtOAc and filtered through a plug of Celite®. The filtrate was washed with saturated ammonium chloride solution and dried over sodium sulfate then concentrated to a black foam. Purification by chromatography (silica, 1:1 petrol-EtOAc) gave the title compound as a black solid (940 mg, 45%); MS (ES+) m/e=360.

Example 25

3-iodo-1-(2-methoxyethoxymethyl)-5-nitro-1-H-indazole: To a solution of 3-iodo-5-nitro-1H-indazole (10.0 g, 34.6 mmol) in THF (50 ml) was added sodium bis(trimethylsilyl)amide (1M in THF, 48.4 mmol, 48.4 ml) and the solution stirred at room temperature for 20 minutes. 2-methoxyethoxymethyl chloride (4.9 g, 39.1 mmol, 4.5 ml) was added and the solution stirred at room temperature for 15 hours. The reaction was quenched with ammonium chloride (30 ml, saturated aqueous) and extracted into ethyl acetate (3×50 ml). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (1:1 EtOAc:hexanes) to give the title compound as an orange solid (6.0 g). ¹H NMR (400 MHz, CDCl₃) δ 3.35 (3H, s), 3.50–3.52 (2H, m), 3.68–3.70 (2H, m), 5.86 (1H, s), 7.69 (1H, d), 8.38 (1H, d), 8.53 (1H, s). MS (ES+) m/e=378.

Example 26

3-iodo-1-(2-methoxyethoxymethyl)-5-nitro-3-phenyl-1H-indazole: To a mixture of 3-iodo-1-(2-methoxyethoxymethyl)-5-nitro-1H-indazole (0.50 g, 1.32 mmol), phenyl boronic acid (0.22 g, 1.80 mmol), potassium phosphate (1.26 g, 5.94 mmol) and 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II), complex with dichloromethane (0.15 g, 0.18 mmol) was added dry dimethoxyethane (8.0 ml) and then heated at 85° C. for 18 hours. Ammonium chloride solution (30 ml, saturated aqueous) was added and extracted into ethyl acetate (3×30 ml). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% MeOH in DCM) to afford the title compound as a yellow solid (0.35 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 3.37 (3H, s), 3.51–3.53 (2H, m), 3.73–3.75 (2H, m), 5.93 (1H, s), 7.50–7.54 (1H, m), 7.57–7.61 (2H, m), 7.73 (1H, d), 7.98 (2H, dd), 8.37 (1H, dd), 9.00 (1H, s).

Example 27

7-Chloro-5-nitro-1H-indazole: To a solution of 2-chloro-6-methyl-4-nitroaniline (5.49 g, 29.4 mmole) in acetic acid (150 mL) was added sodium nitrite (2.03 g, 29.4 mmole) pre-dissolved in water (5 mL). The resulting brown slurry was stirred overnight at room temperature, then at 60° C. for a further 4 hours. The bulk of the solvent was removed by evaporation in-vacuo and the resulting black residue re-dissolved in EtOAc (100 mL) and washed in brine (2×70 mL). The organic layer was dried (MgSO₄), filtered and concentrated to give a mixture of starting material and product 91 mg(1.49 g). The crude mixture was taken through to the next step; ¹H NMR (400 MHz, DMSO) δ 8.25(1H, s), 8.50(1H, s), 8.85(1H, s), 14.30(1H, br s).MS (ES+): m/e=198 (minus Boc).

Example 28

3-Methyl-5-nitro-biphenyl-2-ylamine: A mixture of 2-bromo-6-methyl-4-nitroaniline (100 mg, 0.43 mmole), phenyl boronic acid (81 mg, 0.66 mmole), 2M Na₂CO_(3(aq)) (660 μL), Pd(PPh₃)₄ (4 mg, 0.0033 mmole) in DME(2.4 mL) containing 1.0:1.3 EtOH/H₂O (1.4 mL) was placed in a microwave tube and degassed for 5 minutes. The tube was then capped and irradiated with microwaves (CEM Discover) for 20 minutes at 110° C. The crude reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated NaHCO₃ solution (3×20 mL). The organic layer was dried (MgSO₄), filtered and concentrated in-vacuo to afford a crude solid, this was then purified further by flash chromatography (100% dichloromethane) to yield the desired pure (91 mg) as a bright yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 2.25(3H, s), 4.42(2H, br s), 7.39(3H, m), 7.50(2H, m), 7.97(1H, s), 8.12(1H, s). MS (ES+): m/e=229, (ES−): m/e=227.

Example 29

5-Nitro-7-phenyl-1H-indazole: To a solution of 3-Methyl-5-nitro-biphenyl-2-ylamine (91 mg, 0.39 mmole) in pre-heated glacial acetic acid (4 mL) was added 0.44M sodium nitrite solution (1 mL), in a dropwise fashion. The resulting mixture was stirred overnight at room temperature. The crude product was concentrated in-vacuo and the residue re-dissolved in EtOAc (20 mL) and washed with saturated NaHCO₃ (2×20 mL) and brine (1×20 mL). The organic layer was separated, dried (MgSO₄), filtered and concentrated in-vacuo to yield the desired product (67 mg) as a yellow powder. ¹H NMR (400 MHz, CDCl3) δ 7.50(1H, m), 7.58(2H, m), 7.69(2H, m), 8.33 (2H, m), 8.75(1H, s), 10.55(br s). MS (ES+): m/e=240, (ES−): m/e=238.

Example 30

2-(3-Chloro-2,6-difluorophenyl)-3-cyanopropionic acid methyl ester: Butyllithium (4.1 mL of 2.5M solution in hexanes, 10.3 mmol) was added to a solution of diisopropylamine (1.4 mL, 10.3 mmol) in THF (15 mL) under nitrogen at 0° C. After 15 minutes the reaction mixture was cooled to −78° C. and a solution of 3-chloro-2,6-difluorophenylacetic acid methyl ester (2.15 g, 9.8 mmol) in THF (15 mL) was added. After 30 minutes, iodoacetonitrile (3.5 mL, 49 mmol) was added rapidly to the reaction mixture. The reaction mixture was allowed to warm to 0° C. and ammonium chloride solution added (10 mL, saturated aqueous). The reaction mixture was concentrated and the residue partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organics were dried over magnesium sulfate then concentrated to afford a black oil. The crude product was purified by column chromatography (silica, 25% EtOAc-petrol to EtOAc) to afford the title compound as a pale yellow oil (1.51 g, 59%); ¹H NMR (400 MHz, DMSO) δ 3.06 (1H, dd), 3.19 (1H, dd), 3.67 (3H, s), 4.64 (1H, dd), 7.29 (1H, t), 7.70 (1H, m).

Example 31

4-Amino-2-(3-chloro-2,6-difluorophenyl)-butyric acid methyl ester hydrochloride: To a solution of 2-(3-Chloro-2,6-difluorophenyl)-3-cyanopropionic acid methyl ester (784 mg, 3.0 mmol) and concentrated hydrochloric acid (0.63 mL, 7.55 mmol) in MeOH (5 mL) was added platinum dioxide (69 mg, 0.3 mmol) under nitrogen. The reaction mixture was degassed (5× vacuum cycles) and the nitrogen atmosphere replaced with hydrogen (5× vacuum cycles). The mixture was stirred for 3.5 hours, then filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated and used in the next step without further purification.

Example 32

4-tert-Butylcarbonylamino-2-(3-chloro-2,6-difluorophenyl)-butyric acid: 4-Amino-2-(3-chloro-2,6-difluorophenyl)-butyric acid methyl ester hydrochloride (685 mg, 2.28 mmol) was dissolved in 8M hydrochloric acid solution (10 mL) and the mixture heated at reflux overnight. The mixture was allowed to cool to room temperature, then concentrated. The residue was dissolved in a solution of sodium bicarbonate (1.2 g, 11.4 mmol) in water (15 mL) and THF added (15 mL). The mixture was cooled to 0° C. and di-tert-butyldicarbonate (648 mg, 2.97 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5.5 hours, then concentrated. After dilution with water, the mixture was extracted with ether, then the aqueous phase acidified to pH 4.5 using 2M HCl. The acidified aqueous phase was extracted with EtOAc (×3) and the combined extracts dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (silica, 5% MeOH-DCM) to afford the title compound as a wax (512 mg, 65% two steps); MS (ES−) m/e=348.

Example 33

2-(2,4-Dichlorophenyl)-pentanedioic acid 5-tert-butyl ester 1-methyl ester: Potassium tert-butoxide (767 mg, 6.85 mmol) was added to a solution of methyl 3,4-dichlorophenylacetate (15 g, 68 mmol) in THF (100 mL) at 0° C. under nitrogen. After 15 minutes, the resulting yellow solution was cooled to −78° C. and tert-butylacrylate (11.0 mL, 75 mmol) added over 10 minutes. The reaction mixture was allowed to reach room temperature and stirred overnight. The mixture was concentrated and partitioned between EtOAc and saturated ammonium chloride solution. The aqueous phase was extracted with EtOAc and the combined organics washed with brine, dried (magnesium sulfate) and concentrated to a yellow oil. Purification by column chromatography (silica, 5% ether-petrol) gave the title compound as a pale yellow oil (15.5 g, 65%).

Example 34

4-tert-Butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid methyl ester: 2-(2,4-Dichlorophenyl)-pentanedioic acid 5-tert-butyl ester 1-methyl ester (13 g, 45 mmol) was dissolved in toluene (130 mL) at 0° C. under nitrogen. Diphenylphosphoryl azide (10.6 mL, 49 mmol) and triethylamine (6.8 mL, 49 mmol) were added and the mixture allowed to warm to room temperature over 3 hours. After a further 2 hours, the reaction mixture was concentrated and the residue taken up in EtOAc. The organic phase was washed with 1 w/w % citric acid solution and brine then dried over magnesium sulfate. Concentration at 30° C. gave the acyl azide as a yellow oil which was immediately dissolved in tert-butanol (130 mL) at room temperature. Tin tetrachloride (0.31 mL, 2.68 mmol) was added and the mixture heated at 80° C. for 45 minutes, during which time nitrogen gas was evolved. Upon cooling to room temperature, saturated sodium bicarbonate solution (30 mL) was added and the reaction mixture concentrated. The residue was extracted EtOAc (×3) and the combined extracts washed with brine, dried over magnesium sulfate and concentrated to a yellow oil. Purification by column chromatography (silica, 20% EtOAc-petrol) gave the title compound as a colourless oil (12.8 g, 79%); MS (ES−) m/e=360.

Example 35

4-tert-Butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid: To a solution of 4-tert-butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid methyl ester (12.3 g, 34 mmol) in THF (80 mL)/water (20 mL) was added lithium hydroxide (1.63 g, 68 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the residue diluted with water. After extraction with EtOAc, the aqueous phase was acidified to pH 5 by the addition of 2M aqueous hydrochloric acid solution. The aqueous phase was extracted with EtOAc and the extracts dried over magnesium sulfate. Concentration gave the title compound as a pale brown foam (11.54 g, 98%); ¹H NMR (400 MHz, DMSO) δ 1.35 (9H, s), 1.74–1.81 (1H, m), 2.03–2.10 (1H, m), 2.81 (2H, m), 3.61 (1H, t), 6.86 (1H, m), 7.28 (1H, dd), 7.54 (1H, dd), 7.59 (1H, d), 12.60 (1H, brs); MS (ES−) m/e=346.

Example 36

(3,4-Dichloro-phenyl)-succinic acid 4-tert-butyl ester 1-methyl ester: 2.5M ^(n)Butyllithium in hexanes (37.5 ml, 0.094 mol) was added, in a dropwise fashion, to a solution of diisopropylamine (14.45 ml, 0.103 mol) in tetrahydrofuran (300 ml) at 0° C. The solution was stirred at 0° C. for 20 minutes. The mixture was then cooled to −70° C. and a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (20.54 g, 0.094 mol) in tetrahydrofuran (50 ml) was added dropwise via cannula. The reaction mixture was stirred at −70° C. for 30 minutes. After this time, tert-butyl bromoacetate (45.42 ml, 0.281 mol) was added in a dropwise fashion. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with a saturated solution of NH₄Cl (100 ml). THF was partially removed in vacuo and the mixture was extracted with EtOAc (3×200 ml). The combined organic extrats were washed with brine, dried (MgSO₄) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using as eluent petrol: ether (9:1) to give the title compound in 92% yield.). ¹H NMR (400 MHz, DMSO-d6) δ 1.34 (9H, s), 2.65 (1H, dd), 2.98 (1H, dd), 3.60 (3H, s), 4.08 (1H, m), 7.31 (1H, m), 7.58–7.62 (2H, m); MS (ES⁺): m/e=333.2 (5%); MS (ES⁻): m/e=331.2 (100%), 333.2 (65%), 335.2 (10%).

Example 37

2-(3,4-Dichloro-phenyl)-succinic acid 1-methyl ester: Trifluoroacetic acid (100 ml) was added to a mixture of 2-(3,4-dichloro-phenyl)-succinic acid 4-tert-butyl ester 1-methyl ester (23.64 g, 0.071 mol) and dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo. The crude mixture was kept under vacuo for several hours before being used without further purification in the next step.). ¹H NMR (400 MHz, DMSO-d6) δ 2.66 (1H, dd), 3.01 (1H, dd), 3.59 (3H, s), 4.08 (1H, m), 7.30 (1H, m), 7.56–7.61 (2H, m); MS (ES⁺): m/e=277.1 (100%), 279.1 (65%), 281.0 (10%); MS (ES⁻): m/e=275.1 (50%), 277.1 (30%), 279.1 (5%).

Example 38

3-tert-Butoxycarbonylamino-2-(3,4-dichloro-phenyl)-propionic acid methyl ester: To a solution of 2-(3,4-dichloro-phenyl)-succinic acid 1-methyl ester (0.071 mol) in toluene (200 ml) at 0° C. were successively added diphenylphosphoryl azide (16.82 ml, 0.078 mol) and triethylamine (14.83 ml, 0.106 mol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 1% citric acid (100 ml) and extracted with EtOAc (3×150 ml). The combined organic extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo. The resulting oil was dissolved in tert-butanol (200 ml). Tin(IV) chloride (0.5 ml, 0.004 mol) was added and the mixture was heated to 80° C. for 1 hour (N₂ evolving). The reaction mixture was cooled down to room temperature, quenched with a saturated solution of NaHCO₃. Tert-Butanol was removed in vacuo and the mixture was extracted with EtOAc (3×150 ml). The combined organic extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using as eluent petrol: EtOAc (9:1) to give the title compound (17.35 g) in 70% yield.). ¹H NMR (400 MHz, DMSO-d6) δ 1.31 (9H, s), 3.25–3.40 (1H, m), 3.41–3.52 (1H, m), 3.61 (3H, s), 3.90 (1H, t), 6.95 (1H, t), 7.26 (1H, m); 7.52 (1H, s), 7.60 (1H, d); MS (ES⁺): m/e 348.2 (7%); MS (ES⁻): m/e=457.2 (100%), 459.2 (70%), 461.2 (15%).

Example 39

3-tert-Butoxycarbonylamino-2-(3,4-dichloro-phenyl)-propionic acid: To 3-tert-Butoxycarbonylamino-2-(3,4-dichloro-phenyl)-propionic acid methyl ester (17.11 g, 0.049 mol) in tetrahydrofuran-water (200 ml of each) was added lithium hydroxide (1.18 g, 0.049 mol). The reaction mixture was stirred at room temperature for 6 hours. THF was removed in vacuo and the pH was adjusted to pH 4 with 2M hydrochloric acid. The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic phases were dried (MgSO₄) and concentrated in vacuo. The title compound was obtained as a foam in 89% yield (14.67 g). ¹H NMR (400 MHz, DMSO-d6) δ 1.30 (9H, s), 3.22–3.35 (1H, m), 3.35–3.50 (1H, m), 3.76 (1H, t), 6.84 (1H, t), 7.24 (1H, m); 7.48 (1H, s), 7.58 (1H, d), 12.85 (1H, s); MS (ES⁺): m/e=334.2 (8%); MS (ES⁻): m/e=332.2 (100%), 334.1 (65%), 336.1 (10%).

Example 40

We have prepared other compounds of formula I by methods substantially similar to those described in Examples 1 through 39. The characterization data for these compounds is summarized in Table 5 below and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table 5 below wherein ¹H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 5 Characterization Data for Selected Compounds of Formula I Compound No M+1(obs) R_(t)(min) ¹H NMR 69 376 6.56 2.9–3.3(4H, m), 4.8(1H, brs), 7.45–7.50(1H, m), 7.55–7.65(2H, m), 7.70–7.75(1H, d), 7.80(1H, s), 7.90–7.95(3H, m), 8.08(1H, s), 8.1(1H, s), 10.6–10.7(1H, brs), 13.0–13.2(1H, brs) TFA salt 70 344 5.88 3.1–3.3(4H, m), 5.2(1H, brs), 7.3–7.4(2H, m), 7.6–7.7(2H, s), 7.7–7.9(2H, brs), 8.15–8.2(2H, d), 9.7–10.0(1H, brs), 10.6–10.7 (1H, brs), 13.1–13.3(1H, brs) TFA salt 71 374 5.68 2.99(1H, brs), 3.11(3H, brs), 3.88(3H, s), 5.09(1H, brs), 7.29(1H, d), 7.38(1H, d), 7.53 (2H, m), 7.69, (1H, s), 7.85(3H, brs), 8.06(1H, s), 8.09(1H, s), 9.75(1H, v brs), 10.69(1H, brs), 13.08(1H, brs) TFA salt 72 436 7.31 3.1–3.3(4H, m), 5.2(1H, brs), 7.0–7.1(2H, m), 7.15–7.30(2H, m), 7.40–7.50(2H, m), 7.52–7.60 (2H, m), 7.80(1H, s), 8.0–8.1(3H, m), 8.08(1H, s), 8.1(1H, s), 8.17(1H, s), 10.6–10.7(1H, brs), 13.0–13.2(1H, brs) TFA salt 73 360 6.28 3.1–3.3(4H, m), 5.3(1H, brs), 7.3–7.7(8H, m), 8.0–8.1(3H, m), 8.08(1H, s), 8.1(2H, m), 8.17(1H, s), 9.6–9.8(2H, brs), 10.7–10.8(1H, brs), 13.0–13.2(1H, brs) TFA salt

Example 41

We have prepared other compounds of formula I by methods substantially similar to those described in Examples 1 through 39 and by the general synthetic Schemes I–XV. The characterization data for these compounds is summarized in Table 6 below and includes HPLC, LC/MS (observed), IR, and ¹H NMR data.

¹H NMR data is summarized in Table 6 below wherein ¹H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 6 Characterization data for Selected Compounds of Formula I Compd. M+1 IR No (obs) R_(t) ¹H NMR (cm⁻¹) 97 317 6.0 1.2–2.0(2H, brs), 2.8–2.9(1H, m), 3.2–3.3 1648.3 (1H, m), 3.7–3.8(1H, m), 7.2–7.6(6H, m), 8.0–8.2(2H, m), 10.0–10.3(1H, brs), 12.8–13.1(1H, brs) 98 296 5.2 1.3(1H, m), 1.8–1.9(1H, m), 2.1–2.2(1H, 1655.1 m), 2.6–2.9(1H, m), 3.7–3.9(1H, m), 7.2–7.5 (7H, m), 7.9–8.0(1H, s), 8.0–8.1(1H, s), 10.0–10.1(1H, m), 12.9–13.1(1H, brs) 99 6.8 1.7–2.4(2H, brs), 2.8(1H, m), 3.3(1H, m), 1646.6 3.7–3.8(1H, m), 7.3–7.5(3H, m), 7.6–7.7(2H, m), 8.0(1H, s), 8.2(1H, s), 10.1–10.3 (1H, brs), 12.8–13.1(1H, brs) 100 331 5.9 1.7–1.8(1H, m), 2.0–2.3(1H, m), 2.5–2.6 1646.1 (2H, m), 3.9(1H, m), 7.2–7.6(6H, m), 8.0(1H, s), 8.1(1H, s), 10.0–10.3(1H, br m), 12.6–13.2(1H, brs) 101 347 5.84 1.94–2.00(1H, m), 2.28–2.32(1H, m), 3291, 1671, 1509, 2.76–2.85(2H, m), 4.12(1H, t), 7.27 1458, 1200, 1136, (1H, t), 7.36–7.53(3H, m), 7.55(1H, t), 837, 799, 722 7.74(3H, brs), 8.02(1Hs), 8.11(1H, s), 10.19(1H, s), 13.05(1H, brs) 102 345 6.4 1.6–2.2(2H, br m), 1.8–2.0(1H, m), 2.2–2.3 1651 (1H, m), 2.6(2H, m), 4.0–4.1(1H, m), 7.3–8.2(1H, m), 10.1–10.2(1H, brs), 12.6–1.32(1H, brs) 103 382 6.7 1.8–2.0(1H, m), 2.1–2.3(1H, m), 2.4–2.5 1655 (2H, m), 4.0(1H, m), 7.4–7.6(3H, m), 7.7–7.9(2H, m), 8.0–8.2(2H, m), 10.1–10.3 (1H, brs), 12.6–13.4(1H, brs) 104 364 6.4 1.7–1.9(1H, m), 2.1–2.3(1H, m), 2.4–3.6 1655 (2H, m), 4.0(1H, m), 7.4–7.8(6H, m), 7.9–8.1(2H, m), 10.1–10.3(1H, brs), 12.8–13.2(1H, brs) 105 429 7.52 2.01–2.14(1H, m), 2.30–2.42(1H, m), 3279, 3045, 1681, 2.60–3.73(1H, m), 2.75–2.86(1H, m), 1647, 1550, 1447, 4.08(1H, t), 7.37(1H, d), 7.48(1H, d), 1380, 1306, 1277, 8.01(1H, s), 8.05–8.15(4H, m), 10.38 1181, 1141, 1125, (1H, s), 13.03(1H, brs) 947, 898, 872, 845. 106 363 6.2 1.7–1.9(1H, m), 2.1–2.3(1H, m), 2.6–2.7 1648 (2H, m), 3.0–3.2(1H, m), 4.2–4.4(1H, m), 7.3–7.6(5H, m), 7.9–8.2(2H, m), 10.0–10.4(1H, br m), 12.8–13.2(1H, brs) 107 308 4.24 1.80–1.95(1H, m), 2.12–2.25(1H, m), 670, 1599, 1558, 2.60–2.80(2H, m), 3.57(1H, t), 5.11 1539, 1504, 1201, (2H, s), 6.44(1H, m), 6.54(1H, d), 6.59 1135, 847, 837, (1H, s), 6.80–7.20(3H, m), 7.35–7.50 801. (2H, m), 8.00(1H, s), 8.13(1H, s), 10.01(1H, s), 12.98(1H, brs) 108 339 5.89 1.87–2.05(1H, m), 2.22–2.35(1H, m), 3263, 3056, 2918, 2.60–2.85(2H, m), 3.72(1H, t), 6.95–7.50 1669, 1590, 1509, (7H, m), 7.71(3H, brs), 8.01(1H, 1475, 1436, 1377, s), 8.11(1H, m), 8.00(1H, s), 10.13 1197, 1136, 949, (1H, s), 13.00(1H, brs) TFA salt 879, 841. 109 363 5.61 1.82–1.95(1H, m), 2.30–2.80(3H, m), 3258, 2942, 1672, 4.10–4.23(1H, m), 7.15–7.25(1H, m), 1597, 1557, 1507, 7.30–740(1H, m), 7.46(1H, d), 7.55–7.68 1473, 1443, 1313, (1H, m), 8.00–8.05(2H, m), 9.98 1276, 1201, 1134, (1H, brs), 12.99(1H, brs) 1010, 946, 877, 834, 804. 110 375 6.01 1.95–2.10(1H, m), 2.40–2.50(1H, m), 1672.2, 1508.3, 2.70–2.90(2H, m), 4.06–4.10(1H, m), 1201.4, 1136.1 7.14(1H, t, J 8.0Hz), 7.30–7.43(3H, m), 7.57(1H, s), 7.83(1H, s), 8.19(1H, s), 10.12(1H, s), 12.29(1H, br). 111 352 4.43 1.40–2.90(9H, m), 3.70(1H, t), 7.00–8.10 3254, 2958, 2931, (8H, m), 9.90–10.15(2H, m), 2863, 1727, 1670, 12.90–13.00(1H, m) 1648, 1605, 1557, 1506, 1489, 1442, 1377, 1273, 1228, 1200, 1178, 1131, 1070, 997, 946, 881, 830 112 309 5.68 (CDCl₃) 1.91–2.01(1H, m), 2.22–2.32 1673.4, 1507.4, (1H, m), 2.31(3H, s), 2.62–2.78(2H, m), 1201.6, 1137.97 3.75(1H, t, J 7.2Hz), 7.08–7.10(1H, m), 7.20–7.27(3H, m), 7.38–7.47(2H, m), 8.00(1H, s), 8.12(1H, s), 10.10 (1H, br), 12.97(1H, br) 113 325 5.33 1.78–1.90(1H, m), 2.08–2–20(1H, m), 1673, 1598, 1563, 2.60–2.74(2H, m), 3.85(3H, s), 4.10–4.19 1507, 1464, 1291, (1H, m), 4.95(2H, br hump), 6.85 1245, 1202, 1132, (1H, t), 7.05(1H, d), 7.29(1H, t), 7.36–7.50 1025, 946, 874, (3H, m), 8.00(1H, s), 8.12(1H, s), 838, 801, 754, 9.95(1H, s), 13.00(1H, brs) 738 114 401 6.96 1.77–1.87(H, m), 2.15–2.25(1H, m), 1660, 1596, 1563, 2.50–2.70(2H, m), 3.75–3.81(1H, m), 1507, 1484, 1451, 4.25(2H, br hump), 5.09(2H, s), 6.92 1316, 1262, 1202, (1H, d), 7.01(1H, d), 7.08(1H, s), 1026, 946, 879, 7.20–7.50(8H, m), 7.98(1H, s), 8.10 838, 801, 762, (1H, s), 10.09(1H, s), 13.00(1H, brs) 737, 721, 678 115 311 4.47 1.85–1.96(1H, m), 2.18–2.30(1H, m), 1673, 1631, 1591, 2.60–2.82(2H, 2xm), 3.62–3.70(1H, 1510, 1462, 1201, m), 6.66(1H, d), 6.79–6.85(2H, m), 1137, 949, 874, 7.10(1H, t), 7.24(2H, brs), 7.42 839, 800, 723 (1H, d), 7.48(1H, d), 7.99(1H, s), 8.10 (1H, s), 9.48(1H, brs), 10.07(1H, s), 13.04(1H, brs) 116 361 5.90 1.95–2.00(1H, m), 2.28–2.32(1H, m), 3037, 1741, 1712, 2.43(3H, s), 2.77–2.85(2H, m), 4.11 1474, 1364, 1283, (1H, t), 7.27(1H, t), 7.33–7.46(3H, m), 1155, 1107, 912 7.55(1H, t), 7.72(3H, brs), 8.06(1H, s), 10.18(1H, s), 12.60(1H, brs). TFA salt 117 377 6.99 1.99–2.04(1H, m), 2.26–2.32(1H, m), 3039, 1670, 1199, 2.42(3H, s), 2.67–2.70(1H, m), 2.76–2.80 1134, 1032, 839, (1H, m), 3.78(1H, t), 7.31–7.40 789, 722 (3H, m), 7.62–7.71(5H, m), 8.04(1H, s), 10.19(1H, s), 12.6(1H, brs). TFA salt 118 391 7.35 1.28(3H, t), 1.99–2.02(1H, m), 2.26–2.29 2981, 1670, 1510, (1H, m), 2.67–2.70(1H, m), 2.77–2.82 1200, 1135, 1033, (1H, m), 2.85(2H, q), 3.78(1H, t), 799, 723 7.33–7.41(3H, m), 7.66–7.71(5H, m), 8.06(1H, s), 10.18(1H, s), 12.6(1H, brs). TFA salt 119 439 8.07 1.99–2.02(1H, m), 2.28–2.31(1H, m), 2922, 1670, 1497, 2.67–2.70(1H, m), 2.77–2.81(1H, m), 1201, 1134, 1033, 3.81(1H, t), 7.41(2H, m), 7.49–7.56 799, 722 (4H, m), 7.66–7.68(2H, m), 7.73(3H, brs), 7.89(2H, d), 8.45(1H, s), 10.31 (1H, s), 13.2(1H, brs). TFA salt 120 379 6.4 1.7–1.9(1H, m), 2.1–2.3(1H, m), 2.5(3H, 1649.6 cm−1 s), 2.6–2.7(2H, m), 3.0(1H, m), 4.2–4.4 (1H, m), 7.3–7.4(3H, m), 7.5–7.6(2H, m), 8.1(1H, s), 10.1–10.5(1H, br m), 12.4–12.8(1H, brs) 121 397 7.35 1.74–1.80(1H, m), 2.09–2.16(1H, m), 3271, 1648, 1472, 3.92(1H, t), 7.39–7.52(3H, m), 7.58–8.12 1431, 1303, 1029, (2H, m), 8.13(1H, s), 10.39(1H, brs). 789 122 441 7.49 1.77–1.80(1H, m), 2.13–2.15(1H, m), 2921, 1661, 1498, 2.90–2.92(1H, m), 3.96(1H, t), 7.40–7.52 1471, 1033, 805 (4H, m), 7.60–7.66(2H, m), 8.06 (1H, s), 10.42(1H, brs). 123 476 8.22 1.75–1.77(1H, m), 2.08–2.49(1H, m), 3277, 1646, 1560, 3.01–3.04(2H, m), 3.12–3.16(2H, m), 1507, 1059, 1032 3.91(1H, t), 7.15–7.25(1H, m), 7.26–7.7.27 (4H, m), 7.38–7.41(3H, m), 7.63 (1H, d), 7.65(1H, s), 8.07(1H, s), 10.22 (1H, brs), 12.7(1H, brs). 124 387 7.09 1.81–1.90(1H, m), 2.16–2.33(1H, m), 3278, 1660, 1559, 2.91(1H, m), 3.96(1H, t), 4.50(1H, s), 1495, 1471, 1033, 7.40–7.45(2H, m), 7.51–7.53(1H, m), 1133, 808 7.60–7.67(2H, m), 8.21(1H, s), 10.45 (1H, brs). 125 363 6.1 1.3–1.7(2H, brs), 1.7–1.8(1H, m), 2.1–2.2 — (1H, m), 2.4(3H, s), 2.5–2.6(2H, m), 4.2(1H, m), 7.2(1H, m), 7.4(2H, m), 7.5–7.6 (2H, m), 8.1(1H, s), 10.1–10.3(1H, brs), 12.4–12.7(1H, brs) 126 363 6.1 1.3–1.7(2H, brs), 1.8(1H, m), 2.1–2.2 1646.2 (1H, m), 2.4–2.5(3H, s), 2.5–2.7(2H, m), 4.2(1H, m), 7.2–7.7(5H, m), 8.1(1H, s), 10.1–10.4(1H, brs), 12.4–12.7(1H, brs) 127 454 7.81 1.76–1.99(1H, m), 2.14–2.16(1H, m), 3290, 1658, 1602, 3.88–3.92(1H, m), 6.78(1H, t), 7.27 1553, 1497, 1473, (4H, m), 7.28–7.29(1H, m), 7.61–7.67 1317, 1030, 807, (4H, m), 8.32(1H, s), 8.84(1H, s), 749 10.14(1H, brs), 11.93(1H, brs). 128 510 7.50 .74–1.77(1H, m), 2.07–2.3(1H, m), 2.69 3256, 1660, 1555, (2H, t), 2.94(2H, t), 3.17(3H, m), 3.90 1497, 1471, 1317, (1H, t), 4.11(1H, m) 7.18(1H, m), 7.29–7.41 1023, 698 (6H, m), 7.47(1H, m), 7.61–7.65 (2H, m), 7.97(1H, m), 10.18(1H, brs), 10.28(1H, s), 13.2(1H, brs). 129 344 5.36 1.88–1.97(1H, m), 2.12–2.21(1H, m), 3247, 2925, 1665, 2.43(3H, s), 2.54–2.59(2H, m), 4.02 1578, 1557, 1516, (1H, dd), 7.37–7.42(3H, m), 7.51(1H, 1440, 1306, 1158, d), 7.85(1H, t), 8.08(1H, s), 10.23(1H, 1127, 984, 810, brs), 12.52(1H, brs) 769 130 407 6.99 1.81–1.90(1H, m), 2.15–2.24(1H, m), 3257, 2904, 1650, 2.43(3H, s), 2.66(2H, t), 3.88(3H, s), 1552, 1506, 1465, 4.17(1H, dd), 7.39(2H, s), 7.46(1H, d), 1393, 1312, 1204, 7.52(1H, d), 8.03(1H, s), 10.11(1H, 1189, 1132, 1015, brs), 12.53(1H, brs) 861, 799 131 323 5.90 (CDCl₃) 1.88–1.98(1H, m), 2.21–2.31 670.7, 1511.7, (1H, m), 2.31(3H, s), 2.43(3H, s), 2.60–2.75 1136.6 (2H, m), 3.75(1H, t, J 7.2Hz), 7.08–7.10(1H, m), 7.20–7.27(3H, m), 7.37(2H, s), 8.06(1H, s), 10.08(1H, br), 12.53(1H, br). 132 359 6.22 1.85(1H, m), 2.25(1H, m), 2.6–2.8(2H, 1665, 1487, 1308, m), 4.15(1H, m), 4.2–4.6(2H, brs), 898, 666 7.30(1H, m), 7.40(2H, s), 7.55(1H, m), 7.65(1H, m), 8.10(1H, s), 10.25(1H, s) 133 393 6.60 1.91–1.99(1H, m), 2.16–2.23(1H, m), 3380, 3288, 1675, 2.43(3H, s), 2.84–2.87(1H, m), 4.09 1568, 1516, 1475, (1H, dd), 6.41(1H, brs), 6.92(1H, d), 1440, 1399, 1322, 7.32–7.37(2H, m), 8.08(1H, s), 12.46 1291, 1184, 1137, (1H, brs) 922, 805, 764 134 392 6.46 1.95–2.06(1H, m), 2.22–2.35(1H, m), 3265, 3015, 2970, 2.62–2.71(1H, m), 2.74–2.82(1H, m), 2933, 1736, 1671, 2.82(3H, d), 3.78(1H, t), 7.17(1H, d), 1561, 1518, 1470, 7.23(1H, dd), 7.39(1H, dd), 7.62(2H, 1365, 1304, 1229, brs), 7.64–7.68(2H, m), 7.93(1H, s), 1202, 1133, 1031, 10.03(1H, s), 11.31(1H, s) 953, 874, 836. 135 337 6.45 (CDCl₃) 1.19(3H, t, J 7.6Hz), 1.91–2.03 1673.1, 1201.4, (1H, m), 2.27–2.33(1H, m), 2.43(3H, s), 1137.4 2.62(2H, q, J 7.6Hz), 2.68–2.83(2H, m), 3.73(1H, t, J 7.9Hz), 7.13–7.40 (6H, m), 7.69(3H, br), 8.05(1H, s), 10.08(1H, s), 12.53(1H, br). TFA salt 136 387 7.0 1.7–1.9(1H, m), 2.1–2.3(1H, m), 2.4–2.5 652.7, 1727.2 (3H, s), 2.6–2.7(2H, m), 4.2(1H, m), 7.4(2H, m), 7.5–7.6(2H, m), 8.0–8.1(1H, s), 10.1–10.4(1H, brs), 12.4–12.7(1H, brs) 137 340 4.84 (D₄-MeOH) 2.19(3H, s), 2.26–2.35 3237, 3053, 1660, (1H, m), 2.54(3H, s), 2.54–2.62(1H, 1644, 1542, 1501, m), 2.91–3.03(2H, m), 5.73(1H, t), 1434, 1373, 1317, 6.44(1H, t), 7.39–7.47(3H, m), 7.64 1204, 1127, 835, (1H, d), 8.01(1H, s) 794, 764, 718 138 378 6.15 1.8–1.95(1H, m), 2.15–2.3(1H, m), 2.55–2.7 1659, 1535, 1201 (2H, m), 3.8–3.85(1H, m), 5.25(2H, s), 5.55(2H, brs), 7.15(1H, d), 7.25(1H, d), 7.4(1H, d), 7.6–7.7(2H, m), 7.9(1H, s), 10.1(1H, brs), 12.4–12.7(1H, brs) 139 349 6.19 1.8–1.95(1H, m), 2.1–2.3(1H, m), 2.4–2.5 3237, 1655, 1511, (3H, s), 2.6–2.7(2H, m), 4.1(1H, m), 1183 6.85(1H, m), 6.95(1H, m), 7.3–7.4(2H, m), 8.0–8.05(1H, s), 10.1–10.2(1H, brs), 12.4–12.7(1H, brs) 140 420 6.16 1.8–1.95(1H, m), 2.1–2.3(1H, m), 2.4–2.5 3200, 1661, 1558, (3H, s), 2.5–2.7(2H, m), 4.0–4.1(1H, 799 m), 7.3–7.4(2H, m), 7.45–7.5(1H, m), 7.6–7.75(2H, m), 7.95–8.0(1H, s), 10.1–10.15 (1H, brs), 10.35–10.4(1H, brs), 12.5–12.8(1H, brs) 141 482 7.24 1.7–1.85(1H, m), 2.1–2.25(1H, m), 2.5–2.7 3250, 1637, 1536, (2H, m), 3.9–4.0(1H, m), 7.3–7.4(2H, 1313, 799 m), 7.45–7.7(5H, m), 7.95–8.0(1H, s), 8.0–8.1(2H, m), 10.1–10.2(1H, brs), 10.7–10.85(1H, brs), 12.5–12.8(1H, brs) 142 365 7.34 (CDCl₃) 0.86–0.88(6H, m), 1.79–1.85 1673.3, 1201.6, (1H, m), 1.91–2.00(1H, m), 2.2.25–2.33 1183.8, 1137.6 (1H, m), 2.43(3H, s), 2.43–2.46(2H, m), 2.64–2.78(2H, m), 3.30(2H, br), 3.74 (1H, t, J 7.4Hz), 7.06–7.37(6H, m), 8.03(1H, s), 10.07(1H, s), 12.53(1H, br). 143 398 7.29 1.92–2.04(1H, m), 2.16–2.32(1H, m), 1670, 1512, 1201, 2.52–2.67(1H, m), 2.70–2.80(1H, m), 1135 3.73(1H, t, J=7.4Hz), 7.34(1H, m), 7.52–7.76 (6H, br m), 7.93(1H, s), 8.12(1H, s), 10.26(1H, s), 13.60(1H, brs). 144 443 7.23 1.75–1.83(1H, m), 2.07–2.20(1H, m), 1654, 1582, 1545, 2.40–2.58(2H, m), 3.92(1H, m), 7.37(1H, 1506, 1472, 1031 d, J=8.4Hz), 7.59(1H, d, J=8.3Hz), 7.61(1H, s), 7.73(1H, s), 8.00(1H, s), 8.12(1H, s), 10.20–10.59(1H, br m), 13.19–13.59(1H, brs). 145 477 7.93 1.80(1H, m), 2.18(1H, m), 2.50–2.68 1670, 1585, 1549, (2H, br m), 3.80(1H, m), 7.35(1H, m), 1502, 1472 7.59(3H, m), 7.80(1H, s), 8.01(1H, s). 146 427 8.05 3.04(1H, dd, J=6.2, 12.7Hz), 3.31(1H, 1672, 1600, 1562, m), 3.91(1H, m), 6.12(2H, brs), 7.35–7.48 1202, 1135 (2H, m), 7.51(3H, m), 7.66(4H, m), 8.10(2H, d, J=12.7), 10.31(1H, s), 13.12(1H, brs). 147 377 6.81 1.85–2.10(1H, m), 2.20–2.30(1H, m), 3255, 2922, 1704, 2.47(3H, s), 2.55–2.80(2H, m), 3.77 1677, 1651, 1553, (1H, t), 7.16(1H, s), 7.38(1H, dd), 7.60–7.73 1513, 1473, 1322, (4H, m), 7.90(1H, s), 7.99(1H, s), 1195, 1135, 1085, 10.10(1H, s), 13.09(1H, s) 1032, 942, 866, 841 148 473 7.91 1.95–2.05(1H, m), 2.20–2.35(1H, m), 3073, 2943, 1671, 2.60–2.85(2H, m), 3.79(1H, t), 7.34 1561, 1508, 1472, (1H, m), 7.39(1H, dd), 7.43–7.75(8H, 1419, 1326, 1202, m), 8.09(1H, s), 8.13(1H, m), 10.26 1135, 1058, 1033, (1H, s), 12.93(1H, s) 945, 874, 835. 149 398 6.34 2.15–2.24(1H, m), 2.35–2.44(1H, m), 3268, 3099, 2950, 2.78–2.86(2H, m), 4.12(1H, t), 7.39 1670, 1563, 1506, (1H, dd), 7.49(1H, d), 7.72(3H, brs), 1404, 1327, 1178, 7.86(1H, s), 8.02(1H, d), 8.09(1H, s), 1143, 943, 881, 10.27(1H, s), 13.03(1H, brs) TFA salt 840, 799, 71 150 440 7.74 1.85(1H, m), 2.18(1H, m), 2.52–2.70 1667, 1600, 1558, (2H, m), 3.88(1H, m), 7.40(2H, m), 1492 7.43(3H, m), 7.64(4H, m), 8.09(2H, s,), 10.31(1H, brs), 13.10(1H, brs). 151 421 8.11 1.79–1.89(1H, m), 2.24–2.30(1H, m), 3291.5, 1691.3, 3.09–3.22(2H, m), 3.55(3H, s), 3.60–3.63 1652.8, 1551.8, (1H, m), 5.85(1H, br), 7.20–7.35 1509.1, 1272.7 (4H, m), 7.47(1H, s), 7.85(1H, s), 8.00 (1H, s), 9.36(1H, br), 11.87(1H, br). 152 420 7.55 1.50–1.55(1H, m), 1.90–1.99(1H, m), 1737.4, 1647.81, 2.35(3H, d, J 4.6Hz), 2.74–2.79(1H, 1580.0, 1365.6 m), 2.91–2.96(1H, m), 3.38–3.42(1H, m), 5.10–5.20(1H, br), 5.35–5.45(1H, br), 6.90–7.15(4H, m), 7.20–7.30(1H, s), 7.53(1H, s), 7.77(1H, s), 9.74(1H, s), 9.36(1H, br), 12.13(1H, br). 153 378 6.59 1.91(1H, m), 2.21(1H, m), 2.41(3H, s), 1666, 1597, 1561, 2.53–2.70(2H, br m), 3.88(1H, m), 1506, 1469 6.59–7.10(1H, brs), 7.38(2H, m), 7.43(1H, m), 7.62(2H, m), 7.99(1H, s), 8.09(1H, s), 10.31(1H, brs), 12.98(1H, brs). 154 341 5.80 1.94–2.00(1H, m), 2.28–2.32(1H, m), 1666, 1198, 1135, 2.76–2.95(2H, m), 3.58(1H, t), 3.85 830, 799, 718 (2H, d), 7.20–7.40(4H, m), 7.38(1H, d), 7.55(1H, d), 7.75(3H, brs), 8.02(1Hs), 8.11(1H, s), 10.19(1H, s), 13.05(1H, brs). 155 381 6.8 1.1–1.4(2H, m), 1.6–1.8(1H, m), 2.0–2.1 — (1H, m), 2.4–3.6(2H, m), 3.7–3.8(1H, m), 7.3–7.7(5H, m), 7.9–8.2(2H, m), 10.1–10.2(1H, m), 12.8–13.2(1H, brs) 156 321 5.17 1.80–1.95(2H, m), 2.50–2.65(2H, m), 1649, 1597, 1503, 2.68–2.80(2H, m), 2.85–2.98(2H, m), 1446, 1239, 944 7.22–7.28(1H, m), 7.35–7.50(5H, m), 7.95–8.02(2H, m), 9.25(1H, brs), 12.99(1H, brs) 157 316 5.71 3.17(1H, m), 3.43–3.61(1H, m), 4.08(1H, 1672, 1511, 1201, m), 7.37–7.41(4H, br m), 7.89(3H, brs), 1135 8.12(1H, s), 8.49(1H, s), 8.56(1H, s), 10.58(1H, s), 11.60(1H, brs). 158 468 7.89 1.75–1.95(1H, m), 2.10–2.25(1H, m), 2.57–2.70 3277, 3097, 2938, (1H, m), 2.90–3.10(1H, m), 3.83(1H, 2884, 1647, 1553, t), 4.43(2H, d), 6.48(1H, t), 7.10–7.23(3H, 1509, 1474, 1436, m), 7.29(2H, t), 7.37–7.47(3H, m), 7.58–7.67 1399, 1356, 1311, (2H, m), 8.06(1H, s), 10.02(1H, s), 1236, 1203, 1183, 11.29(1H, s) 1134, 1073, 1030, 991, 958, 873, 833, 811. 159 460 8.9 1.15–1.30(6H, m), 1.55–1.65(1H, m), 1.65–1.90 3288, 2928, 2853, (3H, m), 1.95–2.05(2H, m), 2.10–2.20 1662, 1557, 1470, (1H, m), 2.53–2.60(1H, m), 3.42–3.47(1H, 1449, 1317, 1201, m), 3.83(1H, t), 5.62(1H, d), 7.10–7.20 1182, 1132, 1031, (2H, m), 7.39(1H, dd), 7.60–7.66(2H, m), 840, 805 8.03(1H, s), 9.98(1H, s), 11.20(1H, s) 160 516 7.78 1.75–1.9(1H, m), 2.1–2.25(1H, m), 2.5–2.65 1662, 1546, 741 (2H, m), 3.85–3.9(1H, m), 7.35–7.45 (2H, m), 7.45–7.75(5H, m), 7.95–8.0 (1H, s), 8.0–8.05(1H, m), 8.10(1H, s), 10.3(1H, brs), 10.8–10.95(1H, brs), 12.7–12.8 (1H, brs 161 561 8.90 1.78(1H, m), 2.11(1H, m), 2.48(1H, m), 1603, 1558, 2.93(1H. br m), 3.88(1H, m), 5.07(2H, s), 1533, 1474 6.44(1H, m), 7.11(2H, br m), 7.27(3H, br m), 7.40(6H, br m), 7.60(2H, m), 8.30(1H, s), 8.82(1H, s), 10.09(1H, s), 11.94(1H, brs) 162 490 8.57 1.78(1H, m), 2.12(1H, m), 2.50(2H, m), 1598, 1541, 1480 3.90(1H, m), 6.81(1H, m), 7.20(2H, br m), 7.30(1H, m), 7.38(1H, m), 7.46(1H, m), 7.59(1H, m), 7.67(1H, m), 7.87(1H, s), 8.34(1H, s), 9.11(1H, s), 10.13(1H, brs), 12.04(1H, brs) 163 490 8.58 1.85–1.95(1H, m), 2.15–2.3(1H, m), 2.5–2.7 1660, 1548, 1491 (2H, m), 3.87–3.95(1H, m), 5.7–6.2(2H, brs), 7.20–7.35(4H, m), 7.4–7.45(1H, m), 7.6–7.75(4H, s), 8.35(1H, s), 9.05(1H, s), 10.3(1H, brs), 12.7–12.8(1H, brs 164 479 7.82 2.00–2.08(1H, m), 2.24–2.33(1H, m), 2.64–2.69 2220.9, 1670.9, (1H, m), 2.75–2.82(1H, m), 3.80(1H, 1606.7, 1541.7, t, J 7.5Hz), 7.32–7.41(3H, m), 7.65–7.73 1201.2, 1183.8, (6H, m), 8.33(1H, s), 9.56(1H, s), 10.22 1135.5 (1H, br), 12.32(1H, br) 165 479 8.03 1.78–1.90(1H, m), 2.12–2.21(1H, m), 2.53–2.61 2229.9, 1668.8, (2H, m), 3.89(1H, t, J 7.7Hz), 7.20–7.45 1602.4, 1559.8, (5H, m), 7.63–7.68(2H, m), 7.84–7.86 1476.3, 1201.5, (1H, m), 8.18(1H, m), 8.39(1H, m), 9.36 1134.4 (1H, s), 10.19(1H, br), 12.14(1H, br). 166 534 8.60 1.83–1.92(1H, m), 2.15–2.24(1H, m), 2.53–2.67 2220.9, 1669.3, (2H, m), 3.86(1H, t, J 7.5Hz), 7.29–7.41 1548.0, 1488.5 (5H, m), 7.60–7.67(4H, m), 8.32(1H, s), 9.05(1H, s), 10.17(1H, br), 12.03(1H, br) 167 512 7.40 1.93–2.03(1H, m), 2.21–2.30(1H, m), 3247, 3063, 1685, 2.63–2.79(2H, m), 3.77(H, t), 3.85(3H, 1537, 1470, 1434, s), 7.19(1H, dd), 7.37(1H, dd), 7.43–7.48 1317, 1291, 1189, (2H, m), 7.54(1H, dd), 7.63–7.70(7H, m), 1143, 1040, 846, 7.94(1H, d), 10.22(1H, s), 10.77(1H, s), 799, 718 12.79(1H, s) TFA salt 168 512 7.30 1.93–2.02(1H, m), 2.20–2.30(1H, m), 3196, 3058, 1670, 2.61–2.79(2H, m), 3.77(1H, t), 3.85(3H, 1639, 1598, 1542, s), 7.07–7.10(2H, m), 7.37(1H, dd), 7.43 1511, 1470, 1321, (1H, d), 7.54(1H, dd), 7.63–7.70(5H, m), 1260, 1204, 1184, 7.92(1H, d), 8.06(1H, d), 10.21(1H, s), 1132, 1040, 830, 10.61(1H, s), 12.75(1H, s). TFA salt 794 169 488 7.13 1.94–2.03(1H, m), 2.21–2.31(1H, m), 3222, 3088, 1670, 2.61–2.80(2H, m), 3.78(1H, t), 7.24–7.27 1562, 1475, 1419, (1H, m), 7.38(1H, dd), 7.43(1H, d), 7.56 1332, 1286, 1194, (1H, dd), 7.64–7.70(5H, m), 8.80(1H, dd), 1132, 1030, 840, 7.95(1h, d), 10.23(1H, s), 10.87(1H, s), 794, 712 12.81(1H, s) TFA salt 170 532 8.10 1.87–2.00(1H, m), 2.15–2.38(1H, m), 2.60–2.77 3257, 3226, 1658, (2H, m), 3.79(1H, t), 6.56(1H, s), 1541, 1472, 1322, 7.35–7.39(1H, m), 7.42–7.47(1H, m), 7.54–7.70 1294, 1233, 1202, (6H, m), 8.00–8.16(5H, m), 8.72(1H, 1133, 1031, 958, s), 10.24(1H, s), 10.94(1H, s), 12.80(1H, s) 867, 830. 171 526 7.31 1.93–2.02(1H, m), 2.18–2.31(1H, m), 2.62–2.80 3265, 1655, 1605, (2H, m), 3.77(1H, t), 6.15(2H, s), 1541, 1503, 1473, 6.55(1H, s), 7.08(1H, d), 7.35–7.44(2H, 1439, 1400, 1359, m), 7.51–7.70(6H, m), 7.91(1H, s), 10.21 1324, 1294, 1259, (1H, s), 10.60(1H, s), 12.76(1H, s) 1133, 1037, 931, 875, 812. 172 558 8.46 1.94–2.04(1H, m), 2.18–2.32(1H, m) 2.58–2.70 1736, 1673, 1637, (1H, m), 2.70–2.83(1H, m), 3.78(1H, 1544, 1374, 1365, t), 7.37(1H, dd), 7.42–7.47(2H, m), 7.50–7.56 1228, 1216, 1205, (3H, m), 7.62–7.71(5H, m), 7.79(2H, 1137. d), 7.87(2H, d), 7.97(1H, d), 8.17(2H, d), 10.23(1H, s), 10.83(1H, s), 12.80(1H, s) TFA salt 173 531 8.38 1.78–1.80(1H, m), 2.10–2.14(1H, m), 2.89 3257, 1672, 1593, (1H, m), 3.77(0.5H, t), 3.93(0.5H, t), 7.05 1529, 1477, 1312, (1H, m), 7.31–7.41(5H, m), 7.48(1H, m), 774 7.60–7.65(1H, m), 7.66(1H, s), 7.78(1H, s), 8.14(1H, m), 9.40(1H, brs), 9.67(1H, brs), 10.2(0.5H, brs), 10.25(0.5H, brs), 12.6(1H, brs) 174 507 7.22 1.94–2.02(1H, m), 2.20–2.30(1H, m), 2.61–2.79 2232.8, 1667.8, (2H, m), 3.78(1H, t, J 7.5Hz), 7.36–7.67 1546.7, 1201.5, (5H, m), 7.97–8.22(5H, m), 10.23(1H, 1134.8 br), 11.08(1H, br), 12.86(1H, br). 175 507 7.22 1.91–1.99(1H, m), 2.20–2.30(1H, m), 2.60–2.76 2232.0, 1667.9, (2H, m), 3.81(1H, t, J 7.6Hz), 7.36–7.81 1547.6, 1202.0, (6H, m), 7.98–8.49(4H, m), 8.32(1H, s), 1134.5 10.26(1H, br), 11.03(1H, br), 12.84(1H, br). 176 497 7.83 1.75–1.78(1H, m), 2.09–2.15(1H, m), 2.80–2.89 3263, 1638, 1560, (1H, m), 3.92(1H, t), 7.00(1H, t), 1497, 1312, 1031, 7.29–7.41(4H, m), 7.47–7.52(3H, m), 8.17 692 (1H, s), 9.29(1H, brs), 9.57(1H, brs), 10.22 (1H, brs), 12.45(1H. brs). 177 500 7.38 1.75–1.90(1H, m), 2.10–2.25(1H, m), 2.50–2.65 1663, 1541, 1458 (2H, m), 4.10–4.15(1H, m), 7.18–7.25 (1H, m), 7.35–7.7(6H, m), 7.6–7.75(4H, brs), 7.95–8.15(3H, m), 10.2(1H, br), 10.9 (1H, br), 12.8(1H, br). 178 574 8.54 1.70–1.90(1H, m), 2.05–2.18(1H, m), 2.40–2.60 3491, 3291, 3069, (2H, m), 3.72–3.92(1H, m), 7.10(2H, 2954, 2871, 1674, d), 7.19(1H, t), 7.28(1H, d), 7.35–7.46(4H, 1647, 1549, 1488, m), 7.50–7.70(5H, m), 7.86(1H, d), 7.92 1474, 1439, 1325, (1H, s), 10.24(1H, s), 10.78(1H, s), 12.76 1296, 1279, 1232, (1H, s) 1198, 1133, 1032, 954, 892, 879. 179 500 7.47 1.78(1H, m), 2.05(1H, m), 3.90(1H, m), 1587, 1551, 1473, 7.35(1H, d, J=8.30Hz), 7.42(1H, d, 1324, 1270 J=8.9Hz) 7.46(2H, m), 7.60(3H, m), 7.83 (1H, m), 7.90(3H, m), 10.20(1H, brs), 10.70–10.8(1H, s), 12.56–12.94(1H, brs). 180 518 7.39 1.75–1.93(1H, m), 2.10–2.22(1H, m), 2.38–2.65 3183, 1654, 1593, (2H, m), 3.75–3.95(1H, m), 7.37–7.70 1541, 1499, 1470, (9H, m), 8.05–8.10(1H, m), 10.19–10.27 1434, 1388, 1330, (1H, m), 10.82(1H, s), 12.74(1H, s) 1203, 1185, 1134, 1049, 1032, 958, 905, 876, 838. 181 526 7.85 1.36(3H, t), 1.72–1.90(1H, m), 2.05–2.20 3242, 2919, 1666, (1H, m), 2.38–2.60(2H, m), 3.72–3.92(1H, 1645, 1597, 1518, m), 4.12(2H, q), 7.16(1H, d), 7.35–7.68 1502, 1491, 1473, (8H, m), 7.92–7.96(1H, m), 10.19–10.28 1438, 1390, 1329, (1H, m), 10.71(1H, s), 12.75(1H, s) 1301, 1281, 1235, 1047, 1030, 911, 823. 182 516 7.93 1.75–1.90(1H, m), 2.05–2.20(1H, m), 2.38–2.65 1655, 1553, 1473 (2H, m), 3.85–3.95(1H, m), 7.35–7.70 (7H, m), 7.95–8.02(1H, m), 8.05–8.1(2H, m), 10.2–10.27(1H, m), 10.8(1H, brs), 12.8(1H, s) 183 550 8.44 1.75–1.90(1H, m), 2.05–2.20(1H, m), 2.38–2.65 1643, 1536, 1307 (2H, m), 3.9–3.95(1H, m), 7.35–7.65 (7H, m), 7.80–7.85(1H, m), 8.00–8.1(2H, m), 8.30(1H, s), 10.3(1H, brs), 10.9(1H, brs), 12.8(1H, s) 184 550 8.46 1.78(1H, m), 2.11(1H, m), 3.31(2H, m), 1664, 1643, 1554, 3.90(1H, br m), 7.39(2H, br m), 7.50(1H, 1473 br m), 7.60(2H, m), 7.92(1H, m), 7.98(1H, m), 8.08(2H, m), 10.85–13.10(1H, brs), 12.79(1H, brs). 185 496 7.72 1.70(1H, m), 2.05(1H, m), 2.41(3H, s), 1641, 1587, 1545, 3.30(2H, m), 3.85(1H, br m), 7.27–7.44 1470 (4H, br m), 7.51(1H, m), 7.60(2H, m), 7.85(2H, m), 7.93(1H, s), 10.18(1H, m), 10.61(1H, brs), 12.70(1H, brs). 186 560 8.04 1.78(1H, m), 2.16(1H, m), 3.30(2H, br m), 1644, 1528, 1475 3.88(1H, m), 7.32(2H, m), 7.32(1H, m) 7.41(1H, m), 7.50(2H, m), 7.60(2H, m), 7.85(1H, m), 7.95(1H, s), 8.05(1H, m), 8.21(1H, m), 10.20(1H, m), 10.59–11.09 (1H, brs), 12.37–12.92(1H, brs). 187 510 8.12 1.10(3H, t), 1.70(1H, m), 2.10(1H, m), 3.32 1653, 1542, 1472 (2H, br m), 2.70(2H, q), 3.87(1H, m), 7.35(4H, m), 7.32(1H, m), 7.50(2H, m), 7.60(2H, m), 7.90(1H, s), 7.95(1H, m), 10.20(1H, s), 10.60(1H, s), 12.57–12.88 (1H, brs). 188 524 8.55 0.91(3H, t), 1.62(2H, m), 1.74(1H, m), 2.10 1654, 1541, 1491 (1H, m), 3.30(2H, m), 2.60(2H, q), 3.88(1H, m), 7.35(4H, m), 7.41(1H, m), 7.59(2H, m), 7.93(3H, br m), 10.20(1H, s), 10.59(1H, s), 12.58–12.90(1H, brs). 189 560 8.00 1.70(1H, m), 2.10(1H, m), 3.29(2H, m), 1655, 1541, 1472 3.87(1H, m), 7.32(1H, m), 7.41(1H, m), 7.58(2H, m), 7.77(2H, m), 7.91(1H, m), 7.80(2H, m), 10.65–11.00(1H, brs), 12.50–12.96 (1H, brs). 190 518 7.15 1.82(1H, m), 2.19(1H, m), 2.58(2H, m), 654, 1541, 1507 3.89(1H, m), 7.16(1H, m), 7.29(1H, m), 7.40(4H, m), 7.65(2H, m), 7.77(2H, m), 7.96(1H, m), 10.19(1H, s), 11.55–12.27(1H, brs). 191 554 7.46 1.85(1H, m), 2.19(1H, m), 2.61(2H, m), 1653, 1558, 1507 3.89(1H, m), 7.06(1H, m), 7.18(1H, m), 7.30–7.40(3H, m), 7.61(2H, m), 7.78(1H, m), 7.85(1H, m), 9.97(1H, s), 11.02–11.41 (1H, brs). 192 496 7.49 1.82(1H, m), 2.12(1H, m), 3.25(2H, m), 1655, 1600, 1471 3.75(2H, s), 3.89(1H, m), 7.20(1H, m), 7.34(6H, br m) , 7.51(1H, m), 7.60(2H, m), 7.93(1H, s), 10.20(1H, brs), 10.51(1H, s), 12.10–13.10(1H, brs). 193 483 6.49 (D₄-MeOH) 2.09–2.14(1H, m), 2.40–2.44 3242, 3083, 1675, (1H, m), 2.85–2.90(1H, m), 2.95–3.01 1557, 1511, 1465 (1H, m), 3.79(1H, t), 7.38–7.40(1H, m), 1184, 1132, 846, 7.48(2H, s), 7.55–7.57(1H, m), 7.60–7.65 974, 722 (1H, m), 8.03(2H, d), 8.12(1H, s), 8.83(2H, s) TFA salt 194 483 6.54 (D₄-MeOH) 2.02–2.05(1H, m), 2.30–2.36 3191, 1660, 1542, (1H, m), 2.70–2.80(2H, m), 3.76(1H, t), 1465, 1306, 1117, 7.38–7.54(4H, m), 7.65(2H, s), 8.10(1H, 1030 d), 8.46(1H, d), 8.80(1H, s), 9.20(1H, s) 195 483 7.27 (D₄-MeOH) 1.99–2.06(1H, m), 2.30–2.39 3268, 1670, 1542, (1H, m), 2.70–2.82(2H, m), 3.78(1H, t), 1465, 1317, 1122, 7.39–7.54(4H, m), 7.65–7.68(2H, m), 799, 738 8.07(1H, t), 8.20(1H, s), 8.27(1H, d), 8.77 (1H, d) 196 508 7.94 1.80–1.91(1H, m), 2.10–2.25(1H, m), 2.50–2.70 2232.0, 1669.1, (2H, m), 3.85(1H, m), 5.38(1H, d, J 1602.3, 1573.0, 11.0Hz), 5.55(1H, d J 17.7Hz), 6.81–6.88 1535.7, 1443.5, (1H, m), 7.37–7.73(7H, m), 7.97(2H, s), 1244.62, 1203.3, 8.20(1H, s), 10.26(1H, br), 10.80(1H, br), 1154 12.78(1H, br). 197 511 6.75 1.90–2.10(1H, m), 2.20–2.30(1H, m), 2.60–2.82 1669.8, 1547.8, (2H, m), 3.79(1H, t J 7.3Hz), 4.15 1200.8, 1134.9 (2H, s), 7.00–7.45(4H, m), 7.58–7.80(6H, s), 8.00–8.30(6H, m), 10.27(1H, br), 10.80 (1H, br), 12.83(1H, br). TFA salt 198 511 6.45 1.92–2.04(1H, m), 2.20–2.31(1H, m), 2.60–2.82 1669.6, 1547.8, (2H, m), 3.78(1H, t J 7.0Hz), 4.15 1200.8, 1134.6 (2H, s), 7.36–7.52(3H, m), 7.61–7.66(3H, s), 7.74(3H, br), 7.98(1H, s), 8.00–8.30 (6H, m), 8.11(2H, d, J 7.6Hz), 8.29(3H, br), 10.25(1H, br), 10.82(1H, br), 12.82 (1H, br). TFA salt 199 574 8.55 1.95(1H, m), 2.21(1H, m), 2.67(1H, s), 1597, 1573, 1533, 2.73(1H, m), 3.73(1H, m), 7.07(2H, d, 1300, 1142 J=8.6Hz), 7.13(2H, d, J=8.5Hz), 7.33(1H, m), 7.32(1H, m), 7.35–7.52(4H, br m), 7.55–7.76(5H, br m), 7.91(1H, s), 8.05 (2H, d, J=8.6Hz), 10.20(1H, s), 10.70(1H, s), 12.73(1H, s). 200 550 8.14 1.78(1H, m), 2.10(1H, m), 3.85(1H, m), 1587, 1555, 1324, 7.31(1H, d, J=9.0Hz), 7.37(1H, d, 1128 J=9.0Hz) 7.49(1H, m), 7.58(2H, m), 7.79 (2H, m), 7.95(2H, m), 8.31(1H, m), 8.36 (1H, s), 10.18(1H, s), 10.89–11.18(1H, br s), 12.68–12.89(1H, brs). 201 518 7.72 1.80(1H, m), 2.11(1H, m), 2.55(2H, m), 1598, 1552, 1472, 3.81(1H, m), 5.11–5.97(2H, brs), 7.30 1330, 1125 (1H, d, J=8.3Hz), 7.39(1H, d, J=9.0Hz) 7.50(1H, m), 7.57(3H, m), 7.75(2H, m), 7.91(1H, s), 10.20(1H, s), 10.72–10.10 (1H, brs), 12.81(1H, s). 202 616 8.93 1.78(1H, m), 2.10(1H, m), 3.85(1H, m), 1557, 1473, 1320, 7.35(1H, d, J=8.3Hz), 7.41(1H, d, 1195 J=9.0Hz) 7.50(1H, m), 7.58(3H, m), 8.01 (1H, s), 8.41(1H, s), 8.70(2H, s), 10.25(1H, s), 12.68–13.01 203 568 8.37 1.85(1H, m), 2.07(1H, m), 2.49–2.71(2H, 1551, 1470, 1551, br m), 3.81(1H, m), 6.09–7.89(2H, brs), 1328, 1124 7.35(1H, d, J=8.3Hz), 7.43(1H, d, J=9.0Hz), 7.51(1H, m), 7.60(2H, m), 7.94 (1H, s), 8.02(1H, m), 8.21(1H, m), 8.29(1H, s), 10.23(1H, s), 10.93–11.41(1H, brs), 12.82(1H, s). 204 566 8.29 1.78(1H, m), 2.08(1H, m), 3.89(1H, m), 1586, 1552, 1474, 7.32(1H, d, J=8.3Hz), 7.42(1H, d, 1260, 1162 J=9.0Hz) 7.51(1H, m), 7.60(3H, m), 7.70 (1H, s), 7.95(1H, m), 8.01(1H, m), 8.10(1H, m), 10.23(1H, s), 10.78–11.01 (1H, brs), 12.75(1H, s). 205 506 7.63 1.90–2.04(1H, m), 2.20–2.31(1H, m), 2.60–2.82 1669.1, 1550.1, (2H, m), 3.77(1H, t J 7.4Hz), 4.35 1474.0, 1202.4, (1H, s), 7.36–7.74(9H, m), 7.96(1H, s), 1133.3 8.08(1H, d, J 7.64Hz), 8.16(1H, s), 10.23 (1H, br), 10.88(1H, br), 12.81(1H, br). TFA salt 206 511 7.08 (D₄-MeOH) 2.02–2.07(1H, m), 2.33–2.40 3247, 2950, 1655, (1H, m), 2.72–2.87(2H, m), 2.87(3H, s), 1598, 1537, 1475, 3.81(1H, t), 6.67(2H, d), 7.39–7.53(4H, 1322, 1271, 1184, m), 7.65(1H, s), 7.87(2H, d), 8.01(1H, s) 1132, 825, 753 207 525 7.45 (D₄-MeOH) 1.29(3H, t), 2.03–2.10(1H, 3263, 2966, 1665, m), 2.37–2.43(1H, m), 2.78–2.90(2H, 1603, 1527, 1475, m), 3.23(2H, q), 3.79(1H, t), 6.68(2H, d), 1327, 1265, 1184, 7.38–7.54(4H, m), 7.64(1H, s), 7.86(2H, 1132, 825, 794, 769 d), 8.02(1H, s) 208 528 7.58 1.72–1.80(1H, m), 2.10–2.16(1H, m), 3217, 1639, 1521, 3.90(1H, t), 7.38(1H, d), 7.43(1H, d), 1465, 1347, 1322, 7.51–7.62(4H, m), 7.87(1H, t), 8.00(1H, 1296, 1127, 876, s), 8.49(1H, t), 8.90(1H, s), 10.28(1H, s), 810 12.94(1H, s) 209 511 7.29 1.90–2.03(1H, m), 2.20–2.31(1H, m), 2.58–2.80 3252, 3047, 1671, (2H, m), 2.74(3H, s), 3.77(1H, t), 1604, 1547, 1472, 6.70–6.80(1H, m), 7.15–7.28(3H, m), 7.35–7.45 1431, 1326, 1201, (2H, m), 7.50–7.55(1H, m), 7.60–7.75 1135, 1031, 839. (5H, m), 7.93(1H, s), 10.21(1H, s), 10.56 (1H, s), 12.74(1H, s) TFA salt 210 525 7.68 1.19(3H, t), 1.90–2.05(1H, m), 2.14–2.32 3236, 3035, 1671, (1H, m), 2.55–2.80(2H, m), 3.11(2H, q), 1548, 1472, 1434, 3.76(1H, t), 6.70–6.85(1H, m), 7.18–7.28 1327, 1201, 1134, (3H, m), 7.32–7.45(2H, m), 7.50–7.53(1H, 1031, 953, 835. m), 7.60–7.73(5H, m), 7.93(1H, s), 10.20 (1H, s), 10.55(1H, s), 12.74(1H, s) TFA salt 212 468 8.57 1.80–1.92(1H, m), 2.16–2.28(1H, m), 1665.6, 1611.2, 2.26(3H, s), 2.50–2.67(2H, m), 3.90 1560.2, 1473.4, (1H, t J 7.3Hz), 6.58–6.60(1H, m), 1201.3 7.00–7.70(8H, m), 8.30(1H, s), 8.76 (1H, s), 10.21(1H, br), 11.92(1H, br). 213 472 8.53 1.80–1.90(1H, m), 2.12–2.25(1H, m), 1664.7, 1616.5, 2.50–2.65(2H, m), 3.92(1H, m), 6.56 1554.4, 1533.1, (1H, m), 7.21–7.42(5H, m), 7.62–7.68 1492.2, 1143.5 (3H, m), 8.35(1H, s), 9.15(1H, br), 10.25(1H, br), 12.06(1H, br). 214 579 7.49 1.40(2H, m), 1.51(4H, m), 1.80(1H, 1662, 1545, 1470, m), 2.13(4H, m), 3.50(2H, s), 3.88(1H, 1324, 1032 t), 7.36–7.42(2H, m), 7.46–7.54(3H, m), 7.58–7.63(2H, m), 7.94(1H, s), 7.96(2H, s), 10.27(1H, s), 10.72(1H, s), 12.75(1H, brs). 215 581 7.22 1.78(1H, m), 2.11(1H, m), 2.39(4H, 3227, 1661, 1545, m), 3.55(2H, s), 3.59(4H, m), 7.36–7.42 1437, 1113 (2H, m), 747–7.62(5H, m), 7.95–7.99 (3H, m), 10.20(0.5H, brs), 10.29 (0.5H, brs), 10.73(1H, brs), 12.75(1H, brs). 216 567 7.07 0.99(6H, t), 1.73(1H, m), 2.09(1H, m), 2967, 1655, 1557, 3.30(2H, s), 3.76(0.5H, t), 3.69(0.5H, 1472, 1323, 1055, t), 7.25–7.61(7H, m), 7.92–7.99(3H, m), 1013, 811 10.20(1H, brs), 10.71(1H, brs), 12.75 (1H, brs). 217 562 6.85 1.78(1H, m), 2.11(1H, m), 2.88(1H, 2981, 1668, 1540, m), 3.76(0.5H, t), 3.86(0.5H, t), 5.30 1473, 1323, 1054, (2H, s), 6.92(1H, s), 7.25(1H, s), 7.35–7.43 1013, 815, 722 (2H, m), 7.49–7.61(5H, m), 7.81 (1H, s), 7.92–8.02(3H, m), 10.19(1H, brs), 10.79(1H, brs), 12.75(1H, brs). 218 580 6.37 1.80(1H, m), 2.12(1H, m), 2.32(4H, 1662, 1550, 1469, m), 2.71(4H, m), 2.87(1H, m), 3.51 1324, 1134, 1031. (2H, s), 3.75(0.5H, t), 3.90(o.5H, m), 7.36–7.43(2H, m), 7.46–7.52(5H, m), 7.94–7.97(3H, m), 10.20(0.5H, brs), 10.29(0.5H, brs), 10.71(1H, brs), 12.75 (1H, brs). 219 564 8.20 1.75(1H, m), 2.08(1H, m), 2.85(1H, m), 1657, 1546, 1469, 3.90(1H, m), 7.33(2H, m), 7.51(1H, 1324 m), 7.53–7.60(4H, br m), 7.82(1H, d), 7.95(1H, m), 8.15(1H, d), 8.26(1H, s), 10.27(1H, s), 10.90(1H, brs), 12.74 (1H, brs). 220 524 7.09 1.75(1H, m), 2.09(1H, m), 2.78(3H, s), 1660, 1545, 1491, 2.83(1H, m), 3.89(1H, m), 7.35(1H, d), 1324 7.40(1H, d), 7.50(1H, m), 7.59(2H, m), 7.68(1H, t), 7.95(1H, m), 8.15(1H, d), 8.30(1H, d), 8.61(1H, s), 10.28(1H, s), 10.95(1H, brs), 12.73(1H, brs). 221 560 6.93 1.75(1H, m), 2.10(1H, m), 2.48(2H, m), — 2.81(1H, m), 3.84(1H, m), 7.31(1H, d), 7.41(1H, d), 7.50(1H, m), 7.59(2H, m), 7.80(1H, t), 7.98(1H, m), 8.15(1H, d), 8.35(1H, d), 8.66(1H, s), 10.25(1H, s), 11.05(1H, brs), 12.78(1H, brs). 222 479 9.28 (D₄-MeOH) 1.35(6H, d), 1.99–2.04 1675, 1557, 1496, (1H, m), 2.30–2.39(1H, m), 2.67–2.80 1470, 1189, 1132, (2H, m), 3.00–3.07(1H, m), 3.79(1H, 794 t), 7.31(1H, d), 7.41–7.54(5H, m), 7.67–7.73(2H, m), 7.79(1H, s), 8.36 (1H, s) 223 515 9.55 (D₄-MeOH) 2.00–2.05(1H, m), 2.35–2.40 3226, 1670, 1562, (1H, m), 2.72–2.82(2H, m), 3.78 1495, 1470, 1321, (1H, t), 7.38–7.49(2H, m), 7.50–7.57 1137, 1029, 810 (5H, m), 7.60–7.71(3H, m), 7.75–7.77 (2H, m), 7.91(1H, d), 8.17(1H, s), 8.44(1H, s) 224 507 9.11 (D₄-MeOH) 2.10–2.18(1H, m), 2.42–2.51 3206, 3068, 1665, (1H, m), 2.86–3.03(2H, m), 3.82 1557, 1501, 1475, (1H, t), 7.42(1H, d), 7.51–7.58(3H, 1327, 1301, 1184, m), 7.68(1H, s), 7.73–7.74(2H, m), 1122, 794 8.22(2H, s), 8.41(1H, s) TFA salt 225 365 13.7 1.7–1.8(1H, m), 2.1–2.2(1H, m), 2.8–3.4 1644.2 (2H, m), 3.9–4.0(1H, m), 7.3–7.7 (5H, m), 7.9–8.2(2H, m), 10.1–10.4 (1H, brs), 12.7–13.3(1H, brs) 226 391 7.54 2.06–2.12(1H, m), 2.35–2.50(1H, m), 1670.8, 1199.7, 2.79(6H, s), 2.92–3.06(2H, m), 3.76 1132.7 (1H, t J 7.5Hz), 7.36–7.49(3H, m), 7.66–7.70(2H, m), 8.01(1H, s), 8.11 (1H, s), 9.52(1H, br), 10.26(1H, br), 13.02(1H, br). 227 377 8.75 3.47–3.51(1H, m), 3.85–3.93(1H, m), 1671.4, 1200.1, 4.29(1H, t J 7.2Hz), 7.36–7.51(3H, 1132.3 m), 7.67–7.77(2H, m), 8.03(1H, s), 8.09(1H, s), 9.39(1H, br), 10.43(1H, br), 13.04(1H, br). TFA salt 228 447 8.48 2.01–2.10(1H, m), 2.32–2.41(1H, 3211, 1665, 1598, m), 2.66–2.81(2H, m), 3.78(1H, t), 1562, 1496, 1312, 7.27–7.31(1H, d), 7.35–7.42(3H, 805, 764 m), 7.48–7.56(6H, m), 7.60–7.64 (1H, m), 7.70(1H, d), 7.75(2H, d), 7.90(1H, d), 8.16(1H, s), 8.42(1H, s) D₄-MeOH 229 413 8.10 2.04–2.13(1H, m), 2.34–2.43(1H, 3227, 2966, 1660, m), 2.71–2.86(2H, m), 3.02–3.07 1598, 1557, 1491, (1H, m), 3.79(1H, t), 7.28–7.53(9H, 1312, 1199, 1184, m), 7.71(1H, d), 7.79(1H, s), 8.36 1132, 794 (1H, s) D₄-MeOH 230 439 8.12 2.14–2.22(1H, m), 2.41–2.51(1H, — m), 2.85–3.02(2H, m), 3.82(1H, t), 7.31–7.35(1H, m), 7.41(2H, t), 7.47–7.57 (4H, m), 7.72–7.74(2H, m), 8.22(2H, s), 8.40(1H, s) D₄-MeOH 231 425 8.90 — — 232 465 8.93 2.91(1H, dd), 3.24(1H, dd), 3.78(1H, 3267, 1649, 1613, t), 7.21(1H, d), 7.29(1H, d), 7.37(2H, 1564, 1538, 1493, t), 7.44(1H, t), 7.60–7.65(2H, m), 7.84 1474, 1405, 1330, (1H, d), 8.17(1H, s), 8.40(1H, s), 9.36 1265, 1241, 1204, (1H, s), 10.24(1H, s), 12.14(1H, s). 1134, 1031, 877, 859 233 363 7.50 2.43(3H, s), 2.86(1H, dd), 3.21(1H, 3242, 2918, 1655, dd), 3.74(1H, t), 7.30–7.38(3H, m), 1596, 1560, 1510, 7.59–7.62(2H, m), 8.08(1H, s), 10.21 1473, 1375, 1308, (1H, s), 12.54(1H, s). 1261, 1181, 1133, 1064, 1031, 989, 949, 870, 844. 234 457 8.59 1.81(1H, m), 2.15(1H, m), 2.52(1H, 1662, 1609, m), 2.99(1H, m), 3.91(1H, m), 7.45 1560, 1494, 1282 (3H, m), 7.60(2H, s), 7.69(1H, m), 7.75(1H, s), 7.91(2H, m), 8.43(1H, s), 10.35(1H, s), 12.77–13.56(1H, brs). 235 429 7.32 1.79(1H, m), 2.18(1H, m), 2.50(1H, 1654, 1610, 1493, m), 2.89(1H, m), 3.72(1H, m), 3.89 1281 (3H, s), 7.18(1H, m), 7.28(2H, m), 7.40(2H, m), 7.55(2H, m), 8.01(2H, d, J=8.0Hz), 8.08(2H, d, J=8.2Hz), 8.45 (1H, s), 10.24(1H, s), 12.92–13.45(1H, brs). 236 447 8.57 1.79(1H, m), 2.18(1H, m), 2.51(1H, 1660, 1557, 1492, m), 2.92(1H, m), 3.88(1H, m), 7.20 1320 (1H, m), 7.30(2H, m), 7.40(3H, m), 7.50(4H, m), 7.74(2H, d, J=7.9Hz), 7.81(2H, d, J=8.1Hz), 7.99(2H, d, J= 7.4Hz), 8.53(1H, s), 10.24(1H, s), 12.70–13.48(1H, brs). 237 415 5.21 1.99(1H, m), 2.26(1H, m), 2.63(1H, 1667, 1591, 1493, m), 2.78(1H, m), 3.73(1H, m), 7.22 1325 (1H, m), 7.36(4H, m), 7.57(2H, s), 7.55(2H, m), 7.66(3H, brs), 7.99(2H, d, J=8.1Hz), 8.08(2H, d, J=8.2Hz), 8.45(1H, s), 10.20(1H, s), 13.33(1H, s). TFA salt 238 385 7.46 2.05–2.11(1H, m), 2.32–2.42(1H, 3267, 1665, 1588, m), 2.47(3H, s), 2.68–2.80(2H, m), 1562, 1491, 1312, 3.78(1H, t), 7.24–7.31(2H, m), 7.36–7.42 1173, 789 (3H, m), 7.47–7.53(4H, m), 7.69(1H, d), 7.73(1H, s), 8.35(1H, s) D₄-MeOH 239 455 8.26 2.02–2.11(1H, m), 2.35–2.41(1H, 3227, 1665, 1547, m), 2.67–2.82(2H, m), 3.79(1H, t), 1501, 1265, 1219, 7.27–7.39(4H, m), 7.48–7.55(4H, 1163, 805 m), 7.83(1H, s), 7.96(1H, d), 8.38 (1H, s) D₄-MeOH 240 389 7.27 2.03–2.11(1H, m), 2.33–2.42(1H, 3237, 1660, 1588, m), 2.69–2.84(2H, m), 3.79(1H, t), 1552, 1491, 1465, 7.14–7.18(1H, m), 7.28–7.31(1H, 1306, 1194, 861 m), 7.38(2H, t), 7.47–7.57(5H, m), 7.66(1H, d), 7.77(1H, d), 8.40(1H, s) D₄-MeOH 241 405 7.76 2.15–2.22(1H, m), 2.42–2.51(1H, 3048, 1655, 1486, m), 2.85–3.01(2H, m), 3.82(1H, t), 1214, 1143, 799 7.31–7.35(1H, m), 7.39–7.55(8H, m), 7.87(1H, d), 7.93(1H, s), 8.37 (1H, s) D₄-MeOH, TFA salt 242 315 6.30 2.84(1H, dd), 3.22(1H, dd), 3.75(1H, 3281, 1644, 1597, t), 7.37–7.47(6H, m), 7.99(1H, s), 8.13 1547, 1492, 1442, (1H, s), 10.19(1H, s), 12.97(1H, s). 1341, 1309, 1234, 1093, 1048, 1014, 944, 896, 880, 860, 823. 243 349 7.15 2.93(1H, dd), 3.27(1H, dd), 3.81(1H, 3280, 2926, 1670, t), 7.35–7.40(2H, m), 7.47(1H, d), 1597, 1560, 1507, 7.61–7.64(2H, m), 8.00(1H, s), 8.12 1473, 1369, 1310, (1H, s), 10.24(1H, s), 12.99(1H, s). 1290, 1236, 1202, 1133, 1079, 1031, 945, 878, 855, 838, 819. 244 429 7.32 2.02–2.12(1H, m), 2.33–2.43(1H, 3232, 1711, 1650, m), 2.70–2.85(2H, m), 3.79(1H, t), 1547, 1486, 1424, 3.98(3H, s), 7.28–7.32(1H, m), 7.38 1271, 1250, 1184, (2H, t), 7.48–7.56(4H, m), 7.66(1H, 805 t), 8.07(1H, d), 8.18(1H, d), 8.36(1H, s), 8.59(1H, s) D₄-MeOH 245 335 6.76 2.44(3H, s), 2.86–2.90(1H, m), 3.12–3.17 1654.4, 1566.6, (1H, m), 3.97(1H, t J 6.5Hz), 1510.9, 1307.4 6.88(1H, m), 6.98(1H, m), 7.34–7.41 (2H, m), 8.09(1H, s), 10.29(1H, br), 12.57(1H, br). 246 415 5.49 2.14–2.22(1H, m), 2.41–2.49(1H, 3063, 1680, 1557, m), 2.87–3.01(2H, m), 3.83(1H, t), 1491, 1189, 1143 7.31–7.35(1H, m), 7.41(2H, t), 7.47–7.56 (4H, m), 7.65(1H, t), 8.09(1H, d), 8.16(1H, d), 8.34(1H, s), 8.59 (1H, s) D₄-MeOH, TFA salt 247 349 7.17 2.89(1H, dd), 3.22(1H, dd), 3.77(1H, 3278, 2928, 1650, t), 7.35–7.40(2H, m), 7.46(1H, d), 1597, 1558, 1507, 7.60–7.63(2H, m), 8.00(1H, s), 8.12 1473, 1338, 1311, (1H, s), 10.23(1H, s), 12.98(1H, s). 1236, 1200, 1133, 1077, 1031, 945, 877. 248 414 5.90 2.08–2.15(1H, m), 2.37–2.42(1H, 3263, 1644, 1547, m), 2.74–2.90(2H, m), 3.80(1H, t), 1486, 1383, 1317, 7.29–7.32(1H, m), 7.39(2H, t), 7.47–7.54 1204, 1137, 799 (4H, m), 7.63(1H, t), 7.92(1H, d), 8.17(1H, d), 8.34(1H, s), 8.45 (1H, s) D₄-MeOH 249 385 7.49 1.99(1H, m), 2.29(1H, m), 2.65(3H, 1671, 1606, 1202 s), 2.69(1H, m), 2.80(1H, m), 3.60 (1H, m), 7.29(1H, m), 7.21–7.43(4H, br m), 7.55(2H, m), 7.69(2H, brs), 8.05(2H, m), 8.11(2H, m), 8.53(1H, s), 10.28(1H, s), 13.4(1H, brs). 250 413 6.87 — — 251 453 8.64 1.98–2.06(1H, m), 2.31–2.39(1H, 3217, 1644, 1568, m), 2.47(3H, s), 2.67–2.83(2H, m), 1496, 1465, 1312, 3.78(1H, t), 7.25(1H, d), 7.39–7.42 1199, 1178, 1127, (2H, m), 7.49–7.54(3H, m), 7.67–7.73 974 (3H, m), 8.35(1H, s) D₄-MeOH 252 457 8.55 2.01–2.15(1H, m), 2.31–2.40(1H, 3227, 1650, 1588, m), 2.59–2.83(2H, m), 3.78(1H, t), 1557, 1485, 1470, 7.16(1H, d), 7.41(1H, d), 7.48–7.57 1312, 1137, 1040, (4H, m), 7.65–7.67(2H, m), 7.77(1H, 876 d), 8.41(1H, s) D₄-MeOH 253 475 9.04 2.11–2.18(1H, m), 2.45–2.51(1H, 3227, 1680, 1491, m), 2.82–3.03(2H, m), 3.81(1H, t), 1465, 1194, 1137, 7.41–7.45(2H, m), 7.50–7.58(4H, 846, 805 m), 7.67(1H, s), 7.87(1H, d), 7.94 (1H, s), 8.39(1H, s) D₄-MeOH 254 371 6.55 1.95–2.01(1H, m), 2.28–2.33(1H, m), 3291, 3068, 2924. 2.70–2.83(2H, m), 4.13(1H, t), 4.52 1670, 1554, 1498, (1H, s), 7.27(1H, t), 7.40–7.45(2H, m), 1459, 1306, 1201 7.53–7.58(2H, m), 7.72(3H, brs), 8.22 1137, 1063, 959, (1H, s), 10.30(1H, s), 13.40(1H, s). 840, 801. TFA salt 255 391 7.56 2.67(3H, s), 3.15–3.27(1H, m), 3.45–3.53 3016, 1669, 1564, (1H, m), 4.07(1H, t), 7.37–7.43 1497, 1467, 1408, (2H, m), 7.60–7.71(4H, m), 7.87(3H, 1364, 1324, 1201, brs), 8.54(1H, s), 10.45(1H, s), 13.84 1135, 1033, 951, (1H, s). TFA salt 881, 838, 828. 256 523 9.11 2.00–2.05(1H, m), 2.32–2.42(1H, 2.00–2.05(1H, m), 2.70–2.85(2H, m), 3.79(1H, t), m), 2.32–2.42 7.34(1H, d), 7.42(1H, d), 7.49–7.57 (1H, m), 2.70–2.85 (3H, m), 7.61–7.68(2H, m), 7.83(1H, (2H, m), s), 7.96(1H, d), 8.40(1H, s) D₄-MeOH 3.79(1H, t), 7.34 (1H, d), 7.42(1H, d), 7.49–7.57 (3H, m), 7.61–7.68 (2H, m), 7.83 (1H, s), 7.96(1H, d), 8.40(1H, s) 257 333 6.13 2.87–2.91(1H, m), 3.17–3.22(1H, m), 1664.0, 1507.9, 4.06–4.10(1H, m), 7.19–7.23(1H, m), 1457.7 7.39–7.52(4H, s), 8.01(1H, s), 8.14 (1H, s), 10.35(1H, br), 12.98(1H, br). 258 333 6.24 2.83–2.88(1H, m), 3.13–3.19(1H, m), 1738.7, 1365.7, 4.00–4.03(1H, m), 7.27–7.29(1H, m), 1216.9 7.39–7.52(4H, s), 8.00(1H, s), 8.14 (1H, s), 10.34(1H, br), 12.98(1H, br). 259 396 6.67 2.03–2.11(1H, m), 2.32–2.41(1H, 3283, 2930, 2228, m), 2.67–2.81(2H, m), 3.78(1H, t), 1655, 1609, 1557, 7.28–7.31(1H, m), 7.38(2H, t), 7.46–7.49 1496, 1317, 1194, (3H, m), 7.55(1H, d), 7.87(2H, d), 989, 846 8.15(2H, d), 8.40(1H, s) D₄-MeOH 260 400 5.26 2.16–2.25(1H, m), 2.42–2.51(1H, 3042, 2945, 1670, m), 2.80–2.03(2H, m), 3.84(1H, t), 1496, 1199, 1132, 4.25(2H, s), 7.30–7.56(8H, m), 7.38 820, 794 (1H, t), 7.99–8.02(2H, m), 8.45(1H, s) D₄-MeOH, TFA salt 261 439 5.33 2.16–2.24(1H, m), 2.42–2.52(1H, 3211, 3063, 1665, m), 2.83–2.91(1H, m), 2.96–3.02 1491, 1194, 1132, (1H, m), 3.83(1H, t), 7.32–7.35(1H, 835, 789 m), 7.41(2H, t), 7.47–7.50(3H, m), 7.56(1H, d), 8.17–8.21(4H, m), 8.49 (1H, s) D₄-MeOH, TFA salt 262 414 5.45 — — 263 415 4.96 2.12–2.22(1H, m), 2.42–2.51(1H, 3033, 1657, 1609, m), 2.84–2.92(1H, m), 2.95–3.03 1541, 1495, 1380, (1H, m), 3.84(1H, t), 7.30–7.34(1H, 1315, 1262, 1175, m), 7.40(2H, t), 7.47–7.54(4H, m), 1099, 1016, 995, 7.98(2H, d), 8.14(2H, d), 8.40(1H, s) 955, 865, 842. D₄-MeOH 264 443 5.37 1.88–1.90(1H, m), 2.32–2.35(1H, m), 3036, 1655, 1553, 2.62–2.64(1H, m), 2.70–2.72(1H, m), 1495, 1400, 1319, 2.90–2.94(2H, m), 4.13–4.17(1H, m), 699 7.23–7.27(1H, m), 7.32–7.51(8H, m), 7.78–7.83(3H, m), 8.33(1H, s), 11.01 (1H, brs), 13.10(1H, vbrs). 265 463 8.19 1.88(1H, m), 2.15(1H, m), 2.50(2H, 1661, 1589, m), 3.87(1H, m), 7.06(2H, m), 1521, 1490, 1236 7.18(4H, m), 7.29(2H, m), 7.40(4H, m), 7.50(2H, s), 7.90(2H, m), 8.56(1H, s), 10.20(1H, s), 12.75–13.35(1H, brs). 272 421 4.68 1.95–2.04(1H, m), 2.32–2.41(1H, 3237, 3083, 1665, m), 2.66–2.76(2H, m), 3.83(1H, dd), 1537, 1204, 1137, 7.24(1H, t), 7.44–7.53(3H, m), 7.79 840, 810, 728 (1H, d), 7.98–8.00(2H, m), 8.04(1H, s), 8.47(1H, dd), 8.62(1H, d) D₄-MeOH

Example 42

We have prepared other compounds of formula I by methods substantially similar to those described in Examples 1 through 39 and by the general synthetic Schemes I–VII. The characterization data for these compounds is summarized in Table 7 below and includes HPLC, LC/MS (observed), IR, and ¹H NMR data.

¹H NMR data is summarized in Table 7 below wherein ¹H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1.

TABLE 7 Characterization data for Selected Compounds of Formula I Compd M+1 IR No (obs) R_(t) ¹H NMR (cm⁻¹) 1000 489 7.68 1.79–1.83(1H, m), 2.12–2.24(1H, m), 2.95–3.08 IR(Solid): (2H, m), 3.64(1H, t, J=7.4Hz), 3.71 2967, 2865, (3H, s), 3.76(3H, s), 5.00(2H, s), 6.80–7.49 1715, 1513, (9H, m), 7.99(1H, s), 8.10(1H, s), 9.98 1459, 1262, (1H, s), 12.90(1H, s). 1151, 1081, 1012. 1001 395 6.93 0.72–0.89(3H, m), 1.30–1.50(2H, m), — 1.82–2.30(3H, m), 2.90–3.09(2H, m), 3.32–3.65 2H, m), 3.74(3H, s), 6.85–6.95(2H, m), 7.20–7.50(4H, m), 7.58–8.12(3H, m), 10.00(1H, s), 12.90(1H, s). 1002 355 4.80 1.69–1.81(1H, m), 2.07–2.19(1H, m), 2.45–2.59 IR(Solid): (2H, m), 3.67–3.80(7H, m), 6.82–6.96 1665, 1593, (2H, m), 7.01–7.05(1H, m), 7.46–7.49(2H, 1551, 1508, m), 7.99(1H, s), 8.10(1H, s), 10.00(1H, s), 1455, 1269, 12.90(1H, brs). 1231, 1141, 1026. 1003 443 7.55 1.90–2.30(4H, m), 3.50–3.70(1H, m), 3.71–3.75 IR(Solid): (3H, m), 4.18–4.32(2H, m), 6.86–6.93 1651, 1546, (2H, m), 7.10–7.49(8H, m), 7.95–8.02(1H, 1508, 1455, m), 8.08–8.14(1H, m), 8.23–8.50(1H, m), 1246, 1174, 9.78–10.05(1H, m), 12.92(1H, brs). 1026. 1004 423 6.49 1.85–1.97(1H, m) 2.16–2.33(3H, m), 3.25–3.58 IR(Solid): (8H, m), 3.63–3.69(1H, m), 3.72(3H, 1655, 1627, s), 6.90(2H, d, J=11.58Hz,), 7.31(2H, d, J= 1503, 1465, 11.4Hz), 7.36–7.49(2H, m), 7.99(1H, s), 1431, 1246, 8.11(1H, s), 10.00(1H, s), 12.90(1H, s). 1112. 1005 311 4.85 1.92–2.05(1H, m), 2.20–2.32(1H, m), 2.78–2.88 1672, 1511, (2H, m), 4.07–4.13(1H, m), 6.81(1H, t), 1457, 1193, 6.89(1H, d), 7.11(1H, t), 7.29(1H, d), 7.38–7.50 1137, 838, 816, (2H, m), 8.00(1H, s), 8.12(1H, s), 9.82 800, 756, 723 (1H, s), 9.95(1H, s), 13.00(1H, brs) 1006 309 5.26 1.90–2.08(1H, m), 2.27–2.38(1H, m), 2.43 1672, 1199, (3H, s), 2.65–2.75(1H, m), 2.75–2.85(1H, 1135, 838, 799, m), 3.75–3.82(1H, m), 7.20–7.50(8H, m, + 722, 701 2H br hump), 8.04(1H, s), 10.10(1H, s), 12.57(1H, brs) 1007 339 5.54 1.68–1.80(1H, m), 2.04–2.16(1H, m), 2.45 1674, 1492, (3H, s), 2.55–2.62(2H, m), 3.85(3H, s), 1247, 1201, 4.15–4.20(1H, m), 6.95(1H, t), 7.00(1H, d), 1135, 752, 672 7.20–7.25(1H, m), 7.35–7.48(3H, m), 8.08 (1H, s), 9.91(1H, s), 12.48(1H, brs) 1008 351 6.40 1.78(3H, s), 1.80–1.90(1H, m), 2.18–2.29 3279, 1648, (1H, m), 2.40(3H, s), 2.97–3.05(2H, m), 1553, 1513, 3.69–3.77(1H, m), 7.29(1H, t), 7.34–7.40 1490, 1449, (4H, m), 7.40–7.45(2H, m), 7.86(1H, br t), 1367, 1310, 8.05(1H, s), 10.01(1H, s), 12.51(1H, brs) 995, 803, 773, 741, 696 1009 338 7.29 1.90–2.12(1H, m), 2.21–2.41(3H, m), 3.51 IR(Solid): 1722, (3H, s), 3.69–3.76(1H, m), 7.22–7.50(6H, 1651, 1598, m), 8.00(1H, s), 8.09(1H, s), 9.81(1H, s), 1555, 1508, 12.90(1H, brs). 1450, 1255, 1155, 945. 1010 414 8.65 1.96–2.12(1H, m), 2.24–2.41(3H, m), 3.69–3.83 — (1H, m), 5.05–5.13(2H, m), 7.21–7.48 (6H, m), 7.90(1H, s), 8.11(1H, s), 10.09 (1h, s), 12.91(1H, s). 1011 324 4.95 — 3280, 1703, 1655, 1593, 1551, 1503, 1236. 1012 338 7.29 1.90–2.12(1H, m), 2.21–2.41(3H, m), 3.51 IR(Solid): (3H, s), 3.69–3.76(1H, m), 7.22–7.50(6H, 1722, 1651, m), 8.00(1H, s), 8.09(1H, s), 9.81(1H, s), 1598, 1555, 12.90(1H, brs). 1508, 1450, 1255, 1155, 945. 1013 473 8.22 (CDCl₃) 1.95–2.08(1H, m), 2.45–2.61(4H, — m), 3.23–3.46(2H, m), 3.58–3.65(1H, m), 3.84(3H, s), 4.99–5.19(3H, m), 6.81–7.02 (3H, m), 7.21–7.42(7H, m), 7.92(1H, s), 8.08(1H, s), 9.78(1H, brs) 1014 325 5.34 1.69–1.84(1H, m), 2.06–2.21(1H, m), 2.44–2.58 — (2H, m), 3.75(3H, s), 3.78–3.83(1H, m), 6.78–6.84(1H, m), 6.95–7.01(2H, m), 7.21–7.27(1H, m), 7.35–7.41(1H, m), 7.41–7.47 (1H, m), 7.99(1H, brs), 8.11(1H, brs), 10.08(1H, s), 12.96(1H, brs). 1015 339 5.56 1.68–1.80(1H, m), 2.06–2.20(1H, m), 2.41 1651, 1593, (3H, s), 2.42–2.59(2H, m), 3.75(3H, s), 1555, 1508, 3.78–3.83(1H, m), 6.75–6.83(1H, m), 6.91–7.02 1484, 1303, (2H, m), 7.19–7.28(1H, m) 7.31–7.43 1260, 1146, (2H, m), 8.09(1H, m), 10.10(1H, s), 12.53 1045. (1H, s). 1016 — 5.15 1.70–1.82(1H, m), 2.05–2.15(1H, m), 2.55–2.65 1657, 1599, (2H, m), 2.82(3H, d), 3.83(3H, s), 4.13–4.28 1491, 1415, (1H, m), 5.85(1H, d), 6.92(1H, t), 7.00 1303, 1244, (1H, d), 7.11(1H,d), 7.18–7.28(2H, m), 7.38 1026, 810, 756, (1H, t), 8.00(1H, s), 9.84(1H, s), 11.24(1H, s) 735, 667 1017 325 5.34 1.69–1.84(1H, m), 2.06–2.21(1H, m), 2.44–2.58 — (2H, m), 3.75(3H, s), 3.78–3.83(1H, m), 6.78–6.84(1H, m), 6.95–7.01(2H, m), 7.21–7.27(1H, m), 7.35–7.41(1H, m), 7.41–7.47 (1H, m), 7.99(1H, brs), 8.11(1H, brs), 10.08(1H, s), 12.96(1H, brs). 1018 339 5.56 1.68–1.80(1H, m), 2.06–2.20(1H, m), 2.41 IR(Solid): (3H, s), 2.42–2.59(2H, m), 3.75(3H, s), 1651, 1593, 3.78–3.83(1H, m), 6.75–6.83(1H, m), 6.91–7.02 1555, 1508, (2H, m), 7.19–7.28(1H, m)7.31–7.43 1484, 1303, (2H, m), 8.09(1H, m), 10.10(1H, s), 12.53 1260, 1146, (1H, s). 1045. 1019 487 8.69 1.36(3H, t), 1.78–1.92(1H, m), 2.08–2.20 3280, 1686, (1H, m), 2.43(3H, s), 2.91–3.11(2H,m), 4.06 1648, 1601, (2H, q), 5.00(2H, s), 6.85–7.02(2H, m), 7.20 1494, 1474, (1H, t), 7.25–7.45(9H, m), 8.09(1H, s), 9.85 1453, 1296, (1H, s) 1267, 1248, 1079, 1051, 1009, 771, 750, 694 1020 461 8.22 1.89–2.08(2H, m), 2.25–2.46(5H, m), 4.86–5.03 — (3H, m), 7.10–7.51(11H, m), 7.96–8 1021 461 8.32 1.78–1.93(1H, m), 2.11–2.25(1H, m), 2.42 — (3H, s), 2.92–3.12(2H, m), 4.05(1H, brt, J= 6.3Hz), 4.99(2H, s), 7.11–7.59(12H, m), 8.09(1H, s), 10.13(1H, s), 12.55(1H, s). 1022 327 5.54 1.70–1.86(1H, m), 2.06–2.20(1H, m), 2.42 — (3H, s), 2.42–2.65(2H, m), 4.01–4.18(1H, m), 7.10–7.61(5H, m), 8.09(1H, s), 10.18 (1H, s), 12.51(1H, brs). 1023 401 6.79 2.06(1H, m), 2.35(1H, m), 2.67(1H, m), — 2.77(1H, m), 3.82(3H, s), 3.98(1H, t), 7.10 (2H, d), 7.25–7.57(7H, m), 7.81(2H, d), 8.13 (3H, s), 8.50(1H, s), 10.60(1H, s) HCl salt 1024 461 8.22 1.89–2.08(2H, m), 2.25–2.46(5H, m), 4.86–5.03 — (3H, m), 7.10–7.51(11H, m), 7.96–8 1025 369 5.65 1.75–1.87(1H, m), 2.10–2.25(1H, m), 2.44 1658, 1586, (3H, s), 2.57–2.70(2H, m), 3.79(3H, s), 3.81 1550, 1510, (3H, s), 4.10–4.19(1H, m), 5.20(2H, br hump), 1478, 1431, 6.92–7.02(1H, m), 7.00–7.09(2H, 1307, 1278, m), 7.30–7.40(2H, m), 8.08(1H,s), 10.00 1234, 1202, (1H, s), 12.50(1H, brs) 1172, 1086, 1001, 801, 769, 751 1026 315 5.26 180–1.95(1H, m), 2.10–2.22(1H, m), 2.45 1658, 1564, (3H, s), 2.55–2.65(1H, m), 4.15–4.25(1H, 1511, 1484, m), 6.93–7.00(1H, m), 7.00–7.05(1H, m), 1309, 991, 806, 7.30–7.42(3H, m), 8.07(1H, s), 10.27(1H, 771, 700 s), 12.58 1H, brs) 1027 389 7.10 2.03(1H, m), 2.34(1H, m), 2.67(1H, m), — 2.78(1H, m), 3.90(1H, t), 7.28(1H, m), 7.35–7.45(6H, m), 7.51–7.57(2H, m), 7.92 (2H, m), 7.97(3H, s), 8.49(1H, s), 10.48 (1H, s) HCl salt 1028 371 6.86 2.03(1H, m), 2.35(1H, m), 2.67(1H, m), — 2.78(1H, m), 3.93(1H, t), 7.26–7.58(11H, m), 7.90(2H, d), 8.01(3H, s), 8.52(1H, s), 10.51(1H, s) HCl salt 1029 — 7.72 2.44–2.75(2H, m), 3.09–3.20(2H, m), 4.12–4.20 — (4H, m), 7.21–7.30(2H, m), 7.41–7.51 (2H, m), 7.64–7.75(4H, m), 7.88(1H, m), 8.13(1H, m), 8.27(1H, m), 8.73(1H, s), 9.55(1H, s), 10.50(1H, s), 12.50(1H, s) TFA salt 1030 — 5.82 1.99–2.09(2H, m), 2.62–2.67(2H, m), 3.71–3.78 — (4H, m), 6.95–6.99(2H, m), 7.26–7.31 (4H, m), 7.68–7.83(3H, m), 8.28–8.33(2H, m), 9.01(1H, s), 10.05(1H, s), 12.02(1H, s) TFA salt 1031 — 7.19 2.26–2.32(2H, m), 2.67–2.78(2H, m), 3.69–3.78 — (4H, m), 6.87–6.99(3H, m), 7.20–7.46 (4H, m), 7.70(1H, m), 7.83(1H, d), 8.14 (1H, m), 8.33(1H, m), 9.35(1H, s), 10.09 (1H, s), 12.15(1H, s) TFA salt 1032 313 5.23 1.69–1.82(1H, m), 2.05–2.20(1H, m), 2.45–2.61 1660, 1589, (2H, m), 4.05–4.19(1H, m), 7.10–7.61 1555, 1498, (6H, m), 7.99(1H, s), 8.13(1H, s), 10.18 1479, 1227. (1H, s), 12.99(1H, brs). 1033 309 5.46 1.70–1.88(1H, m), 2.10–2.23(1H, m), 2.42 1651, 1593, (3H, s), 2.45–2.62(2H, m), 3.69–3.89(1H, 1560, 1503, m), 7.20–7.48(7H, m), 8.08(1H, s), 10.15 1479, 1446, (1H, brs), 12.50(1H, brs). 1308. 1034 309 5.45 1.70–1.88(1H, m), 2.10–2.23(1H, m), 2.42 1651, 1593, (3H, s), 2.45–2.62(2H, m), 3.69–3.89(1H, 1560, 1503, m), 7.20–7.48(7H, m), 8.08(1H, s), 10.15 1479, 1446, (1H, brs), 12.50(1H, brs). 1308. 1035 315 5.25 1.75–1.90(1H, m), 2.08–2.24(1H, m), 2.2 3273, 1656, (3H, s), 2.53–2.65(2H, m), 3.96–4.02(1H, 1663, 1551, m), 7.15–7.20(1H, m), 7.30–7.45(3H, m), 1511, 1483, 7.45–7.53(1H, m), 8.10(1H, s), 10.18(1H, 1450, 1309, s), 12.61(1H, brs) 1237, 992, 866, 805, 786, 752, 701, 669 1036 428 7.07 1.70–1.83(1H, m), 2.09–2.23(1H, m), 3.15–3.52 — (2H, m), 3.79–3.90(1H, m), 4.42–4.53 (2H, m), 7.15–7.61(11H, m), 8.49(1H, s), 8.84–8.95(1H, m), 10.23(1H, brs). 1037 299 4.85 1.83–1.97(1H, m), 2.02–2.14(1H, m), 2.43 1659, 1566, (3H, s), 2.54–2.66(2H, m), 3.93–4.02(1H, 1511, 1484, m), 6.27(1H, s), 6.41(1H, s), 7.25–7.42 1449, 1308, (2H,m), 7.56(1H, s), 8.08(1H, s), 10.19(1H, 1011, 993, 936, s), 12.57(1H, brs) 876, 807, 791, 770, 740 1038 400 7.43 1.90(1H, m), 2.07–2.25(1H, m), 2.26(3H, — s), 2.56–2.67(2H, m), 3.81(1H, m), 6.59 (1H, m), 7.09(1H, m), 7.24–7.48(9H, m), 8.29(1H, s), 8.75(1H, s), 10.10(1H, s), 11.92(1H, s) 1039 404 7.41 2.27(1H, m), 2.64–2.72(2H, m), 3.81(1H, — m), 4.02(1H, m), 6.56(1H, m), 7.22–7.44(9H, m), 7.62(1H, d), 8.34(1H, s), 9.15(1H, brs), 10.15(1H, brs), 12.07(1H, brs) 1040 414 7.24 1.71–1.82(1H, m), 2.12–2.25(1H, m), 2.46–2.61 1651, 1593, (2H, m), 3.86(1H, brt, J=6.6Hz), 7.05–7.12 1527, 1489, (1H, m), 7.20–7.28(1H, m), 7.29–7.48 1455, 1308, (6H, m), 7.52–7.65(2H, m), 7.89(1H, d, J= 1231, 1146. 8.0Hz), 8.56(1H, s), 10.25(2H, brs). 1041 404 5.44 1.67–1.75(1H, m), 2.06–2.22(1H, m), 2.42–2.60 — (2H, m), 3.78–3.88(1H, m), 6.69–6.75 (1H, m), 7.19–7.59(8H, m), 7.90–8.00(2H, m), 10.18(1H, s), 10.60(1H, brs), 12.70 (1H, brs). 1042 428 6.03 1.65–1.83(1H, m), 2.10–2.22(1H, m), 2.5 3277, (2H obscured), 3.80–3.88(1H, m), 4.75 1650, 1630, (2H, d), 7.20–7.57(10H, m), 7.82–7.95(2H, 1602, 1543, m), 8.08(1H, s), 9.01(1H, s), 10.13(1H, s), 1507, 1489, 12.77(1H, brs) 1313, 1232, 1202, 1180, 1135, 799, 715, 695, 668 1043 420 5.86 1.61–1.80(1H, m), 2.08–2.11(1H, m), 3.10–3.60 — (2H, m), 3.79–3.88(1H, m), 7.10–7.60 (8H, m), 7.81–8.08(3H, m), 10.18(1H, s), 10.80(1H, brs), 12.76(1H, brs). 1044 420 5.95 1.61–1.80(1H, m), 2.08–2.11(1H, m), 3.10–3.60 1651, 1536, (2H, m), 3.79–3.88(1H, m), 7.10–7.60 1498, 1412, (8H, m), 7.81–8.08(3H, m), 10.18(1H, s), 1322, 1284. 10.80(1H, brs), 12.76(1H, brs). 1045 490 6.42 1.78–1.90(1H, m), 2.20–2.36(1H, m), 3.23–3.50 1647, 1546, (2H, m), 4.17–4.24(1H, m), 7.09–7.28 1468, 1439, (2H, m), 7.32–7.62(3H, m), 7.80–7.91(2H, 1422, 1318, m), 8.10(1H, s), 10.20(1H, brs), 10.80(1H, 1282 brs), 12.75(1H, brs). 1046 490 6.44 1.78–1.90(1H, m), 2.20–2.36(1H, m), 3.23–3.50 1647, 1546, (2H, m), 4.17–4.24(1H, m), 7.09–7.28 1468, 1439, (2H, m), 7.32–7.62(3H, m), 7.80–7.91(2H, 1422, 1318, m), 8.10(1H, s), 10.20(1H, brs), 10.80(1H, 1282 brs), 12.75(1H, brs). 1047 481 7.50 1.82–1.96(1H, m), 2.24–2.39(1H, m), 2.52–2.65 3308, 1669 (2H, m), 4.20–4.29(1H, m), 7.15–7.26 1603, 1559, (2H, m), 7.28–7.40(2H, m), 7.45(1H, t), 1535, 1473, 7.56–7.67(1H, m), 7.80–7.90(1H, m), 8.20 1443, 1328, (1H, s), 8.36(1H, s), 9.36(1H, s), 10.20 1270, 1237, (1H, brs), 12.13(1H, s). 1218, 1188, 1127, 994, 876, 806, 784, 666 1048 481 4.48 1.82–1.96(1H, m), 2.24–2.39(1H, m), 2.52–2.65 3308, 1669, (2H, m), 4.20–4.29(1H, m), 7.15–7.26 1603, 1559, (2H, m), 7.28–7.40(2H, m), 7.45(1H, t), 1535, 1473, 7.56–7.67(1H, m), 7.80–7.90(1H, m), 8.20 1443, 1328, (1H, s), 8.36(1H, s), 9.36(1H, s), 10.20 1270, 1237, (1H, brs), 12.13(1H, s). 1218, 1188, 1127, 994, 876, 806, 784, 666 1049 420 6.00 1.61–1.80(1H, m), 2.08–2.11(1H, m), 3.10–3.60 — (2H, m), 3.79–3.88(1H, m), 7.10–7.60 (8H, m), 7.81–8.08(3H, m), 10.18(1H, s), 10.80(1H, brs), 12.76(1H, brs). 1050 420 6.59 1.13–1.95(11H, m), 2.12–2.25(1H, m), 1651, 1551, 2.39–2.62(2H, m), 2.84–2.96(1H, m), 3.67–3.88 1484, 1441, (1H, m), 7.15–7.61(7H, m), 7.89(1H, 1327 s), 10.03–10.15(2H, m), 12.52(1h, brs). 1051 444 6.60 1.69–1.83(1H, m), 2.07–2.23(1H, m), 3.19–3.50 1670, 1646, (2H, m), 3.78–3.89(1H, m), 4.80(2H, 1598, 1536, s), 6.90–7.59(12H, m), 8.01(1H, s), 10.15 1489, 1303, (1H, brs), 10.48(1H, brs), 12.68(1H, brs). 1231. 1052 369 6.91 1.70–1.82(1H, m), 2.11–2.24(1H, m), 2.44–2.59 2975, 2885, (2H, m), 3.82–3.91(1H, m), 7.18–7.60 1660, 1555, (10H, m), 7.83–7.95(1H, m), 8.50(1H, s), 1489, 1384, 10.22(1H, s), 1317, 1255, 1146 1053 369 6.94 1.70–1.82(1H, m), 2.11–2.24(1H, m), 2.44–2.59 — (2H, m), 3.82–3.91(1H, m), 7.18–7.60 (10H, m), 7.83–7.95(1H, m), 8.50(1H, s), 10.22(1H, s), 13.20( 1H, brs). 1054 411 7.25 1.77–1.87(1H, m), 2.16–2.27(1H, m), 2.55–2.66 1658, 1628, (2H, m), 3.82–3.90(1H, m), 7.12–7.50 1602, 1589, (8H, m), 7.81–7.88(1H, m), 8.20(1H, s), 1560, 1533, 8.43(1H, s), 9.34(1H, s), 10.16(1H, s), 1479, 1330, 12.15(1H, s). 1307, 1265, 1238, 1202, 1180, 1134, 799, 786, 729, 699, 682. 1055 411 7.26 1.77–1.87(1H, m), 2.16–2.27(1H, m), 2.55–2.66 1670, 1603, (2H, m), 3.82–3.90(1H, m), 7.12–7.50 1559, 1479, (8H, m), 7.81–7.88(1H, m), 8.20(1H, s), 1329, 1203, 8.43(1H, s), 9.34(1H, s), 10.16(1H, s), 1181, 1137, 12.15(1H, s). 799, 723, 700, 675 1056 441 7.40 1.84–1.93(1H, m), 2.27–2.38(1H, m), 2.55–2.65 1668, 1560, (2H, m), 4.20–4.30(1H, m), 7.15–7.25 1496, 1473, (1H, m), 7.36–7.44(1H, m), 7.50–7.66(5H, 1443, 1321, m), 7.87–7.95(2H, m), 8.39(1H, s), 10.30 1269, 1218, (1H, brs), 13.20(1H, brs). 993, 957, 825, 807, 777, 749, 720, 698. 1057 441 7.38 1.84–1.93(1H, m), 2.27–2.38(1H, m), 2.55–2.65 1669, 1559, (2H, m), 4.20–4.30(1H, m), 7.15–7.25 1496, 1473, (1H, m), 7.36–7.44(1H, m), 7.50–7.66(5H, 1443, 1320, m), 7.87–7.95(2H, m), 8.39(1H, s), 10.30 1269, 1218, (1H, brs), 13.20(1H, brs). 1202, 993, 807, 776, 749, 720, 699, 675.

Example 43 AKT-3 Inhibition Assay

Compounds were screened for their ability to inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM NaCl, 1 mM DTT and 3% DMSO. Final substrate concentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μM peptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays were carried out at 30° C. and 45 nM AKT. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of AKT, DTT, and the test compound of interest. 55 μl of the stock solution was placed in a 96 well plate followed by addition of 2 μl of 1 mM DMSO stock containing the test compound (final compound concentration 30 μM). The plate was pre-incubated for about 10 minutes at 30° C. and the reaction initiated by addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTF. Rates of reaction were obtained using a Molecular Devices SpectraMax Plus plate reader over a 15 minute read time at 30° C. Compounds showing greater than 50% inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC₅₀ values.

The following compounds were shown to have K_(i) values less than 1 μM for Akt-3 (Compound numbers correspond to the compound numbers listed in Table 1.): I-59, I-60, I-61, I-62, I-64, I-67, I-70, I-73, I-74, I-97 through I-106, I-108 through I-110, I-112, I-115 through I-122, I-124 through I-127, I-129 through I-136, I-138 through I-141, I-141 through I-145, I-147, I-149, I-153, I-155, I-160 through I-175, I-177 through I-189, I-193 through I-210, I-212 through I-227, I-231 through I-234, I-242, I-243, I-245, I-247, I-251 through I-254, I-256 through I-258, I-1005, I-1006, I-1014, I-1022, I-1043 through I-1047, I-1049 and I-1054.

The following compounds were shown to have K_(i) values between 1.0 and 10.0 μM for AKT-3 (Compound numbers correspond to the compound numbers listed in Table 1.): I-5, I-16, I-35, I-40, I-43, I-48 through I-51, I-53 through I-56, I-58, I-63, I-68, I-71, I-72, I-76, I-77, I-78, I-83, and 1–85, I-107, I-111, I-113, I-114, I-123, I-128, I-137, I-142, I-150 through I-152, I-154, I-156 through I-159, I-176, I-191, I-192, I-235, I-236, I-241, I-250, I-255, I-259, I-1017, I-1018, I-1023, I-1028, I-1038, I-1039, I-1041, I-1048, I-1050 through I-1052, I-1055 and I-1056.

The following compounds were shown to have K_(i) values between 10.0 and 20.0 μM for AKT-3 (Compound numbers correspond to the compound numbers listed in Table 1.): I-2, I-37, I-52, I-65, I-66, I-79, I-82, I-94, and I-95, I-146, I-190, I-1040, I-1053 and I-1057.

Example 44 PDK-1 Inhibition Assay

Compounds were screened for their ability to inhibit PDK-1 using a radioactive-phosphate incorporation assay (Pitt and Lee, J. Biomol. Screen., (1996) 1, 47). Assays were carried out in a mixture of 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 2 mM DTT. Final substrate concentrations in the assay were 40 μM ATP (Sigma Chemicals) and 65 μM peptide (PDKtide, Upstate, Lake Placid, N.Y.). Assays were carried out at 30° C. and 25 nM PDK-1 in the presence of ˜27.5 nCi/μL of [γ-³²P]ATP (Amersham Pharmacia Biotech, Amersham, UK). An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP, and the test compound of interest. 15 μl of the stock solution was placed in a 96 well plate followed by addition of 1 μl of 0.5 mM DMSO stock containing the test compound (final compound concentration 25 μM, final DMSO concentration 5%). The plate was preincubated for about 10 minutes at 30° C. and the reaction initiated by addition of 4 μl ATP (final concentration 40 μM).

The reaction was stopped after 10 minutes by the addition of 100 μL 100 mM phosphoric acid, 0.01% Tween-20. A phosphocellulose 96 well plate (Millipore, Cat no. MAPHNOB50) was pretreated with 100 μL 100 mM phosphoric acid, 0.01% Tween-20 prior to the addition of the reaction mixture (100 μL). The spots were left to soak for at least 5 minutes, prior to wash steps (4×200 μL 100 mM phosphoric acid, 0.01% Tween-20). Alter drying, 20 μL Optiphase ‘SuperMix’ liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

Compounds showing greater than 50% inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC₅₀ values.

The following compounds were shown to have a K_(i) of less than 1 μM for PDK-1 (Compound numbers correspond to the compound numbers listed in Table 1.): I-100, I-106, I-109, I-110, I-117, I-119, I-120, I-121, I-123, I-125, I-126, I-127, I-130, I-132, I-136, I-138, I-139, I-141, I-162, I-165, I-167, I-168, I-169, I-171, I-172, I-173, I-174, I-179, I-181, I-182, I-189, I-193, I-194, I-195, I-197, I-198, I-206, I-207, I-230, I-231, I-234 through I-238, I-240, I-241, I-242, I-248 through I-251, I-253, I-259 through I-265, I-272, I-1006, I-1022, I-1023, I-1026, I-1027, I-1028, I-1032, I-1034, I-1035, I-1041, I-1043 through I-1046, I-1048, I-1049, I-1052, I-1053, I-1056 and I-1057.

The following compounds were shown to have a K_(i) of between 1 μM and 3 μM for PDK-1 (Compound numbers correspond to the compound numbers listed in Table 1.): I-98, I-101, I-107, I-112, I-115, I-118, I-122, I-124, I-129, I-137, I-140, I-147, I-158, I-160, I-164, I-166, I-170, I-175, I-176, I-177, I-180, I-185, I-186, I-187, I-188, I-199, I-108, I-212, I-213, I-225, I-228, I-233, I-239, I-1000, I-1005, I-1007, I-1018, I-1036, I-1038, I-1040, I-1054 and I-1055.

The following compounds were shown to have a K_(i) of greater than 3 μM for PDK-1 (Compound numbers correspond to the compound numbers listed in Table 1.): I-16, I-33, I-54, I-99, I-102, I-105, I-111, I-113, I-114, I128, I-131, I-133, I-134, I-135, I-142, I-145, I-148, I-150, I-153, I-154, I-155, I-156, I-159, I-161, I-163, I-178, I-183, I-184, I-190, I-191, I-196, I-200, I-201 through I-204, I-222, I-226, I-227, I-229, I-232, I-233, I-247, I-254, I-257, I-258, I-1000, I-1014 through I-1021, I-1024, I-1025, I-1029, I-1030, I-1031, I-1033, I-1037, I-1039, I-1042, I-1047, I-1050, I-1051 and I-1054.

Example 45 ROCK Inhibition Assay

Compounds were screened for their ability to inhibit ROCK using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). Reactions were carried out in 100 mM HEPES pH 7.5, 10 mM MgCl2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 13 μM ATP (Sigma chemicals) and 200 FM peptide (KKRNRTLSV, American Peptide, Sunnyvale, Calif.). Assays were carried out at 30° C. and 200 nM ROCK. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 400 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ROCK, DTT and the test compound of interest. 56 μl of the test reaction was placed in a 384 well plate followed by addition of 1 μl of 2 mM DMSO stock containing the test compound (final compound concentration 30 μM). The plate was preincubated for about 10 minutes at 30° C. and the reaction initiated by addition of 10 μl of enzyme (final concentration 100 nM). Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showing >50% inhibition versus standard wells containing DMSO, but no compound, were titrated and IC50's determined using a similar protocol.

The following compounds were shown to have a K_(i) of less than 1 μM for ROCK (Compound numbers correspond to the compound numbers listed in Table 1.): I-5, I-6, I-8, I-20, I-25, I-35, I-54, I-69, I-98, I-99, I-100, I-103 through I-107, I-109, I-110, I-120, I-123, I-125, I-126, I-129, I-132, I-137, I-136, I-141, I-142, I-144, I-145, I-153, I-1002, I-1005, I-1006, I-1007, I-1008, and I-1018.

The following compounds were shown to have a K_(i) of between 1 μM and 3 μM for ROCK (Compound numbers correspond to the compound numbers listed in Table 1.): I-4, I-7, I-9, I-24, I-26, I-27, I-31 through I-34, I-38, and I-41.

The following compounds were shown to have a K_(i) of greater than 3 μM for ROCK (Compound numbers correspond to the compound numbers listed in Table 1.): I-12, I-13, I-15, I-16, I-23, I-28, I-29, I-30, O-102, I-118, I-139, I-140, I-1003, I-1014, and I-1019.

Example 46 PKA Inhibition Assay

Compounds were screened for their ability to inhibit PKA using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM NaCl, 1 mM DTT and 3% DMSO. Final substrate concentrations in the assay were 50 μM ATP (Sigma Chemicals) and 80 μM peptide (Kemptide, American Peptide, Sunnyvale, Calif.). Assays were carried out at 30° C. and 18 nM PKA. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP, and the test compound of interest. 55 μl of the stock solution was placed in a 96 well plate followed by addition of 2 μl of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 5 μM). The plate was preincubated for 10 minutes at 30° C. and the reaction initiated by addition of 5 μl of ATP (final concentration 50 μM). Initial reaction rates were determined with a Molecular Devices SpectraMax Plus plate reader over a 15 minute time course. IC50 and Ki data were calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0a for Macintosh, GraphPad Software, San Diego Calif., USA).

The following compounds were shown to have a K_(i) of less than 1 μM for PKA (Compound numbers correspond to the compound numbers listed in Table 1.): I-2, I-35, I-40, I-43, I-48, I-51, I-52, I-54, I-55, I-56, I-59, I60, I-67, I-69, I-73, I-76 through I-78, I-85, I-93, I-97, I-98 through I-110, I-113, I-116 through I-136, I-138 through I-141, I-143 through I-145, I-147, I-149, I-153, I-155 through I-169, I-172, I-174, I-175, I-177 through I-189, I-193 through I-201, I-203 through I-210, I-226, I-227, I-230 through I-237, I-240, I-242 through I-247, I-249, I-252, I-254, I-260, I-261, I-263, I-1006, I-1022, I-1023, I-1026, I-1028, I-1033, I-1034, I-1039, I-1041, I-1043 and I-1044.

The following compounds were shown to have a K_(i) between 1 μM and 5 μM on PKA (Compound numbers correspond to the compound numbers listed in Table 1.): I-6, I-24, I-84, I-92, I-202 and I-1053

Example 47 p70S6K Inhibition Assay

Compounds were screened for their ability to inhibit p70S6K using a radioactive-phosphate incorporation assay at Upstate Biotechnology (Pitt and Lee, J. Biomol. Screen., (1996) 1, 47). Assays were carried out in a mixture of 8 mM MOPS (pH 7.0), 10 mM MgAcetate, 0.2 mM EDTA. Final substrate concentrations in the assay were 15 μM ATP (Sigma Chemicals) and 100 μM peptide (KKRNRTLTV, Upstate Ltd., Dundee, UK). Assays were carried out at 30° C. and in the presence of p70S6K (5–10 mU, Upstate Ltd., Dundee, UK) and [γ-³³P]ATP (Specific activity approx. 500 cpm/pmol, Amersham Pharmacia Biotech, Amersham, UK). An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP, and the test compound of interest. 15 μL of the stock solution was placed in a 96 well plate followed by addition of 1 μL of 40 μM or 8 μM DMSO stock containing the test compound, in duplicate (final compound concentration 2 μM or 0.4 μM, respectively, final DMSO concentration 5%). The plate was preincubated for about 10 minutes at 30° C. and the reaction initiated by addition of 4 μL ATP (final concentration 15 μM).

The reaction was stopped after 10 minutes by the addition of 5 μL 3% phosphoric acid solution. A phosphocellulose 96 well plate (Millipore, Cat no. MAPHNOB50) was pretreated with 100 μL 100 mM phosphoric acid, 0.01% Tween-20 prior to the addition of the reaction mixture (20 μL). The spots were left to soak for at least 5 minutes, prior to wash steps (4×200 μL 100 mM phosphoric acid, 0.01% Tween-20). After drying, 20 μL Optiphase ‘SuperMix’ liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

Percentage inhibition of compounds at 2 μM and 0.4 μM was calculated by comparing p70S6K activity with standard wells containing the assay mixture and DMSO without test compound.

Compounds showing high inhibition versus standard wells were titrated to determine IC₅₀ values.

While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example. 

1. A compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from halogen, CN, N(R⁴)₂, or T-R; T is selected from a valence bond or a C₁₋₆ alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO₂—; each R is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5–7 membered saturated, partially unsaturated, or aromatic ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R² is selected from Q-C(R)(Q-Ar)R³, wherein: R and R³ optionally form a 5–7 membered saturated or partially unsaturated ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C₁₋₄ alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5–7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵, Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; R′ is an optionally substituted C₁₋₆ aliphatic group; each R⁴ is independently selected from R, COR, CO₂R, CON(R)₂, SO₂R, SO₂N(R)₂, or Ar¹; each R⁵ is independently selected from R or Ar; V¹, V² and V³ are each independently C(R⁶); each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR, SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂, OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or SO₂N(R⁴)₂; and each Ar¹ is independently selected from an optionally substituted 5–7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when V¹, V², and V³ are each CH and R¹ is hydrogen then R³ is other than R′, Q-OC(O)R⁵, or OCH₂phenyl.
 2. The compound according to claim 1, wherein: R¹ is selected from halogen, N(R⁴)₂, or optionally substituted C₁₋₆ aliphatic; and R² is Q-C(R)(Q-Ar)R3, wherein: R and R³ optionally form a 5–7 membered saturated or partially unsaturated ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R³ is selected from R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and Ar is an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or all optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 3. The compound according to claim 2, wherein: R¹ is selected from chloro, bromo, fluoro, NH₂, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, or d t-butyl; and R³ is selected from CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, or NHCH₂-imidazol-4-yl.
 4. The compound according to claim 1, wherein: R¹ is hydrogen; and R² is Q-C(R)(Q-Ar)R³, wherein: R and R³ optionally form a 5–7 membered saturated or partially unsaturated ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R³ is selected from Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and Ar is an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 5. The compound according to claim 4, wherein: R³ is selected from OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, or NHCH₂-imidazol-4-yl.
 6. The compound according to claim 1, wherein said compound is selected from the group consisting of:


7. A compound of formula IIb:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is T-Ar; T is selected from a valence bond or a C₁₋₆ alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO₂—; each R is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5–7 membered saturated, partially unsaturated, or aromatic ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R² is Q-C(R)(Q-Ar)R³, wherein: R and R³ optionally form a 5–7 membered saturated or partially unsaturated ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C₁₋₄ alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5–7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R³ is selected from R′, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵, Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; R′ is an optionally substituted C₁₋₆ aliphatic group; each R⁴ is independently selected from R, COR⁵, CO₂R⁵, CON(R⁵)₂, SO₂R⁵, SO₂N(R⁵)₂, or Ar¹; each R⁵ is independently selected from R or Ar; V¹, V² and V³ are each independently C(R⁶); each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR, SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂, OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or SO₂N(R⁴)₂; and each Ar¹ is independently selected from an optionally substituted 5–7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when V¹, V², and V³ are each CH, T is a valence bond, and R² is Q-C(R)(Q-Ar)R³, wherein Ar is an optionally substituted phenyl ring, then R³ is other than Q-OR⁵ or C(O)NH₂.
 8. The compound according to claim 7, wherein: R¹ is T-Ar, wherein: T is selected from —NHC(O)—, —NH—, —NHCH₂—, NHSO₂—, —CH₂NH—, —C≡—, —CH₂— or —CH₂CH₂—; and Ar is an optionally substituted 5–6 membered aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and R² is Q-C(R)(Q-Ar)R³, wherein: R³ is R′, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; each Q is independently selected from a valence bond, —CH₂—, or —CH₂CH₂—; and Ar is an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 9. The compound according to claim 8, wherein: R³ is CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.
 10. The compound according to claim 7, wherein: T is a valence bond; and R² is Q-C(R)(Q-Ar)R³, wherein: R and R³ optionally form a 5–7 membered saturated or partially unsaturated ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R³ is Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and Ar is an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 11. The compound according to claim 10, wherein: R³ is CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂(t butyl), phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.
 12. The compound according to claim 7, wherein said compound is selected from the group consisting of:


13. The compound according to claim 7, wherein said compound has the formula V:

or a pharmaceutically acceptable salt thereof.
 14. A composition comprising a compound according to either of claim 1 or 7, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 15. The composition according to claim 13, additionally comprising a therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
 16. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity comprising the step of contacting the kinase with a compound according to acyone of claims 1 through
 13. 